Anti-c10orf54 antibodies and uses thereof

ABSTRACT

The present disclosure relates generally to anti-C10orf54 antibodies, including antibody-drug conjugates comprising the antibodies, and methods of their use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority of U.S. ProvisionalApplication Ser. No. 61/934,615, filed Jan. 31, 2014, and U.S.Provisional Application Ser. No. 61/832,135, filed Jun. 6, 2013, theentire contents of which are each incorporated herein by reference.

FIELD

The present disclosure relates generally to anti-C10orf54 antibodies,including antibody-drug conjugates comprising the antibodies, andmethods of their use.

BACKGROUND

C10orft54 is a single-pass type I transmembrane protein that is 311amino acids in length and includes a signal sequence and one IgV-likedomain in its intracellular region. It is potentially a member of the B7family of proteins and it has approximately 24% sequence identity toB7-H1/PD-L1 (Flajnik et al., Immunogenetic 64:571-590 (2012)). The mouseortholog to C10orf54 is known as V-region Immunoglobulin-containingSuppressor of T Cell Activation (VISTA; also known as PD-L3). VISTA wascloned from a library of CD4 positive regulatory T cells (T_(reg)) (Wanget al., JEM 208(3):577-592 (2011)). VISTA is primarily expressed onhematopoietic cells, and VISTA expression is highly regulated on myeloidantigen-presenting cells (APCs) and T cells (Wang et al., supra).

VISTA appears to have functional activities that are nonredundant withother Ig superfamily members and may play a role in the development ofautoimmunity and immune surveillance in cancer. For example, expressionof a VISTA-Ig fusion protein has been shown to inhibit T cellproliferation and cytokine production in vitro and overexpression ofVISTA on MCA105 tumor cells interferes with a host's protectiveantitumor immunity (Wang et al., supra). Moreover, administration of aVISTA-specific monoclonal antibody enhanced CD4 positive T cell responsein vivo and the development of autoimmunity (Wang et al., supra).Monoclonal antibodies against C10orf54 have also been shown to preventacute graft-versus-host disease in mice (Flies et al., J. Immunology187(4):1537-1541 (2011)).

Citation or discussion of a reference herein shall not be construed asan admission that such is prior art to the present invention.

SUMMARY

In a first aspect, provided herein are antibodies that bind to C10orf54,including a C10orf54 polypeptide, a C10orf54 polypeptide fragment or aC10orf54 epitope, collectively referred to herein as anti-C10orf54antibodies. Also provided herein are anti-C10orf54 antibodies that areconjugated to drugs as antibody-drug conjugates (ADCs), including ADCsof the formula A-L-CTX, wherein A is an antibody, L is a linker, and CTXis cytotoxin. In some embodiments the anti-C10orf54 antibodies arehumanized antibodies that bind to a C10orf54 polypeptide, a C10orf54polypeptide fragment or a C10orf54 epitope. In certain embodiments, theanti-C10orf54 antibody comprises a VH domain, VL domain, VH CDR1, VHCDR2, VH CDR3, VL CDR1, VL CDR2, and/or VL CDR3 of monoclonal antibody175A, 76E1 or 141A described herein, or a humanized variant thereof. Incertain embodiments, the anti-C10orf54 antibody can further comprise aVH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and/or VL FR4 ofa human germline immunoglobulin amino acid sequence or a variantthereof.

In certain embodiments, the antibody comprises less than six CDRs. Insome embodiments, the antibody comprises or consists of one, two, three,four, or five CDRs selected from the group consisting of VH CDR1, VHCDR2, VH CDR3, VL CDR1, VL CDR2, and/or VL CDR3. In specificembodiments, the antibody comprises or consists of one, two, three,four, or five CDRs selected from the group consisting of VH CDR1, VHCDR2, VH CDR3, VL CDR1, VL CDR2, and/or VL CDR3 of the monoclonalantibody 175A, 76E1 or 141A described herein, or a humanized variantthereof. In specific embodiments, the antibody further comprises a VHFR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and/or VL FR4 of ahuman germline immunoglobulin amino acid sequence or a variant thereof.

In specific embodiments, the antibody is a humanized antibody, amonoclonal antibody, a recombinant antibody, an antigen binding fragmentor any combination thereof. In particular embodiments, the antibody is ahumanized monoclonal antibody, or antigen binding fragment thereof, thatbinds to a C10orf54 polypeptide (e.g., a cell surface-expressed orsoluble C10orf54), a C10orf54 fragment, or a C10orf54 epitope.

In a second aspect, provided herein are antibodies, including humanizedantibodies, (i) that competitively block (e.g., in a dose-dependentmanner) an anti-C10orf54 antibody provided herein from binding to aC10orf54 polypeptide (e.g., a cell surface-expressed or solubleC10orf54), a C10orf54 fragment, or a C10orf54 epitope and/or (ii) thatbind to a C10orf54 epitope that is bound by an anti-C10orf54 antibody(e.g., humanized anti-C10orf54 antibodies) provided herein. In otherembodiments, the antibody competitively blocks (e.g., in adose-dependent manner) monoclonal antibody 175A, 76E1 or 141A describedherein or a humanized variant thereof from binding to a C10orf54polypeptide (e.g., a cell surface-expressed or soluble C10orf54), aC10orf54 fragment, or a C10orf54 epitope. In other embodiments, theantibody binds to a C10orf54 epitope that is bound (e.g., recognized) bymonoclonal antibody 175A, 76E1, or 141A described herein or a humanizedvariant thereof (e.g. humanized anti-C10orf54 antibodies).

In certain embodiments, the anti-C10orf54 antibodies (e.g., humanizedanti-C10orf54 antibodies) provided herein are conjugated orrecombinantly fused to a diagnostic agent, detectable agent ortherapeutic agent. In some aspects, the therapeutic agent is achemotherapeutic agent (e.g., a cystotoxic agent such as cytotoxin). Insome aspects, the detectable agent is a radioisotope, an enzyme, afluorescent compound, a bioluminescent compound or a chemiluminescentcompound. In certain embodiments, the anti-C10orf54 antibodies providedherein are conjugated to drugs as antibody-drug conjugates (ADCs). Insome aspects, the antibody-drug conjugate (ADC) is of the formulaA-L-CTX, wherein A is an antibody, L is a linker, and CTX is acytotoxin.

In certain embodiments, provided are compositions comprising ananti-C10orf54 antibody (e.g., humanized anti-C10orf54 antibodies)described herein. In some embodiments, the compositions comprise anantibody-drug conjugate wherein the antibody is an anti-C10orf54antibody. Also provided herein are pharmaceutical compositionscomprising an anti-C10orf54 antibody, including a humanizedanti-C10orf54 antibody, provided herein.

In a third aspect, provided are isolated nucleic acid molecules encodinga VH chain, VL chain, VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3,VL CDR1, VL CDR2, and/or VL CDR3 of anti-C10orf54 antibodies, includinghumanized anti-C10orf54 antibodies, that bind to a C10orf54 polypeptide,a C10orf54 polypeptide fragment, or a C10orf54 epitope. In certainembodiments, the nucleic acid molecule encodes a VH domain, VL domain,VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and/or VL CDR3 ofmonoclonal antibody 175A, 76E1 or 141A described herein, or a humanizedvariant thereof. In certain embodiments, the nucleic acid moleculefurther encodes a VH FR1, VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VLFR3, and/or VL FR4 of a human germline immunoglobulin amino acidsequence or a variant thereof. Also provided herein are vectors and hostcells comprising the nucleic acid molecules encoding an anti-C10orf54antibody (e.g., humanized anti-C10orf54 antibodies), as well as methodsof producing an anti-C10orf54 antibody by culturing the host cellsprovided herein under conditions that promote the production of theanti-C10orf54 antibody.

In a fourth aspect, provided herein are methods of treating, preventingor alleviating a disease, disorder or condition, including one or moresymptoms of a disease, disorder or condition, comprising administering atherapeutically effective amount of an anti-C10orf54 antibody, includingan antibody-drug conjugate (ADC) comprising an anti-C10orf54 antibody,provided herein to a subject, thereby treating, preventing oralleviating the disease, disorder or condition, including one or moresymptoms of the disease, disorder or condition. In some embodiments theanti-C10orf54 antibodies are humanized antibodies that bind to aC10orf54 polypeptide, a C10orf54 polypeptide fragment or a C10orf54epitope. In one embodiment, the disease, disorder or condition is causedby or otherwise associated with C10orf54, including by or associatedwith C10orf54-expressing cells (e.g., tumor cells, myeloid-derivedsuppressor cells (MDSC), suppressive dendritic cells (suppressive DC),and/or regulatory T cells (T regs)). In certain embodiments, the diseaseis a cancer, such as a leukemia, a bladder cancer or a fibrosarcoma. Inone embodiment, the leukemia is an acute myeloid leukemia (AML). Inother embodiments, the disease is graft-versus-host disease (GVHD).Additional methods provided include using an anti-C10orf54 antibody withC10orf54 binding activity for C10orf54-expressing cells, providedherein, for example, as an unconjugated antibody or conjugated antibody(ADC), including to inhibit and/or kill the C10orf54-expressing cells(e.g., with anti-tumor activity to mediate an anti-tumor effect). Incertain embodiments, the anti-C10orf54 antibodies, including ADCscomprising the anti-C10orf54 antibodies, provided herein inhibitC10orf54-mediated suppressor activity on T cells (e.g., to allow aneffective anti-tumor immune response). In certain embodiments, theanti-C10orf54 antibodies provided herein directly killC10orf54-expressing cells (e.g., C10orf54-bearing tumor cells,myeloid-derived suppressor cells (MDSC), suppressive dendritic cells(suppressive DC), and/or regulatory T cells (T regs)), for example, viaantibody-dependent cellular cytotoxicity (ADCC) and/orcomplement-dependent cytotoxicity (CDC) In certain embodiments, antibodydrug conjugates (ADCs) comprising anti-C10orf54 antibodies providedherein directly kill C10orf54-expressing cells including by binding tocells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressorcells (MDSC), suppressive dendritic cells (suppressive DC), and/orregulatory T cells (T regs)), for example, by allowing internalizationof the cytotoxic drug. In any of the above embodiments, theanti-C10orf54 antibody can be a humanized anti-C10orf54 antibodyprovided herein that binds to a C10orf54 polypeptide, a C10orf54polypeptide fragment or a C10orf54 epitope.

In a fifth aspect, provided herein are methods of inhibiting the growthof cells and/or killing cells having cell surface expression of C10orf54comprising contacting the cells with an effective amount of ananti-C10orf54 antibody or antibody-drug conjugates provided herein. Inone embodiment, the cell is a regulatory T cell (e.g., a CD4⁺ Foxp3⁺regulatory T cell). In other embodiments, the cell is a myeloid-derivedsuppressor cell (e.g., a CD11b⁺ or CD11b^(high) myeloid-derivedsuppressor cell) or a suppressive dendritic cell (e.g., a CD11b⁺ orCD11b^(high) dendritic cell). In other embodiments, the cell is acancerous or pre-cancerous cell. Additional methods provided includeusing an anti-C10orf54 antibody with C10orf54 binding activity forC10orf54-expressing cells provided herein, for example, as anunconjugated antibody or conjugated antibody (ADC) including to inhibitand/or kill C10orf54-expressing cells (e.g., with anti-tumor activity tomediate an anti-tumor effect). In certain embodiments, the anti-C10orf54antibodies, including ADCs comprising the anti-C10orf54 antibodies,provided herein inhibit C10orf54-mediated suppressor activity on T cells(e.g., to allow an effective anti-tumor immune response). In certainembodiments, the anti-C10orf54 antibodies provided herein directly killC10orf54-expressing cells (e.g., C10orf54-bearing tumor cells,myeloid-derived suppressor cells (MDSC), suppressive dendritic cells(suppressive DC), and/or regulatory T cells (T regs)), for example, viaantibody-dependent cellular cytotoxicity (ADCC) and/orcomplement-dependent cytotoxicity (CDC) In certain embodiments, antibodydrug conjugates (ADCs) comprising anti-C10orf54 antibodies providedherein directly kill C10orf54-expressing cells including by binding tocells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressorcells (MDSC), suppressive dendritic cells (suppressive DC), and/orregulatory T cells (T regs)), for example, by allowing internalizationof the cytotoxic drug. In any of the above embodiments, theanti-C10orf54 antibody can be a humanized anti-C10orf54 antibodyprovided herein that binds to a C10orf54 polypeptide, a C10orf54polypeptide fragment or a C10orf54 epitope.

In a sixth aspect, provided herein are methods of modulating an immuneresponse in a subject comprising administering an effective amount of ananti-C10orf54 antibody (e.g., a humanized anti-C10orf54 antibody)provided herein to a subject. In one embodiment, the modulatingcomprises increasing T cell activation. In other embodiment, themodulating comprises increasing T cell proliferation. In anotherembodiment, the modulating comprises increasing cytokine production.

In a seventh aspect, provided herein are methods for detecting C10orf54in a sample comprising contacting the sample with an anti-C10orf54antibody (e.g., a humanized anti-C10orf54 antibody) provided herein,such as an antibody that comprises a detectable agent. In certainembodiments, the sample comprises a cell expressing C10orf54 on itssurface.

In an eighth aspect, provided herein are methods of treating cancerscomprising administering to a subject an anti-C10orf54 antibody or anantibody-drug conjugate (ADC) comprising an anti-C10orf54 (e.g., an ADCof the formula A-L-CTX, wherein A is the antibody, L is a linker, andCTX is a cytotoxic agent) in a therapeutically effective amount,including in an amount effective to kill a C10orf54-expressing cell(e.g., tumor cell, myeloid-derived suppressor cell (MDSC), suppressivedendritic cell (suppressive DC), and/or regulatory T cell (T reg)). Insome embodiments the cancer is acute myeloid leukemia (AML). In any ofthe above embodiments, the anti-C10orf54 antibody can be a humanizedanti-C10orf54 antibody provided herein that binds to a C10orf54polypeptide, a C10orf54 polypeptide fragment or a C10orf54 epitope.

In a ninth aspect, provided herein are methods of killingC10orf54-expressing cells (e.g., tumor cells, myeloid-derived suppressorcells (MDSC), suppressive dendritic cells (suppressive DC), and/orregulatory T cells (T reg)) comprising contacting a C10orf54-expressingcell (e.g., tumor cell, myeloid-derived suppressor cell (MDSC),suppressive dendritic cell (suppressive DC), and/or regulatory T cell (Tregs)) with an amount of an anti-C10orf54 antibody or an antibody-drugconjugate (ADC) comprising an anti-C10orf54 antibody (e.g., an ADC ofthe formula A-L-CTX, wherein A is the antibody, L is a linker, and CTXis a cytotoxic agent) effective to kill the cell (e.g., tumor cell,myeloid-derived suppressor cell (MDSC), suppressive dendritic cell(suppressive DC), and/or regulatory T cell (T reg)). In someembodiments, the tumor cell is an AML cell. In any of the aboveembodiments, the anti-C10orf54 antibody can be a humanized anti-C10orf54antibody provided herein that binds to a C10orf54 polypeptide, aC10orf54 polypeptide fragment or a C10orf54 epitope.

In a tenth aspect, provided herein is a kit comprising an anti-C10orf54antibody (e.g., a humanized anti-C10orf54 antibody) that binds to aC10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54epitope provided herein. In some embodiments, the kits comprise anantibody-drug conjugate (ADC) wherein the antibody is an anti-C10orf54antibody (e.g., a humanized anti-C10orf54 antibody).

Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

The term “about” or “approximately” means within 20%, such as within10%, or within 5% (or 1% or less) of a given value or range.

As used herein, “administer” or “administration” refers to the act ofinjecting or otherwise physically delivering a substance as it existsoutside the body (e.g., an anti-C10orf54 antibody provided herein) intoa patient, such as by mucosal, intradermal, intravenous, intramusculardelivery and/or any other method of physical delivery described hereinor known in the art. When a disease, or a symptom thereof, is beingtreated, administration of the substance typically occurs after theonset of the disease or symptoms thereof. When a disease, or symptomsthereof, are being prevented, administration of the substance typicallyoccurs before the onset of the disease or symptoms thereof.

As used herein, an “agonist” of C10orf54 refers to a molecule that iscapable of activating or otherwise increasing one or more of thebiological activities of C10orf54, such as in a cell expressing C10orf54or in a cell expressing a C10orf54 ligand, such as a C10orf54 receptor.In some embodiments, an agonist of C10orf54 (e.g., an agonistic antibodyprovided herein) may, for example, act by activating or otherwiseincreasing the activation and/or cell signaling pathways of the cellexpressing a C10orf54 or a C10orf54 receptor, thereby increasing aC10orf54-mediated biological activity of the cell the relative to theC10orf54-mediated biological activity in the absence of agonist. Incertain embodiments the antibodies provided herein are agonisticanti-C10orf54 antibodies.

The term “alkyl,” as used herein, means a straight, branched chain, orcyclic (in this case, it would also be known as “cycloalkyl”)hydrocarbon containing from 1-10 carbon atoms. Examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl,n-nonyl, and n-decyl. In certain embodiments, alkyl groups areoptionally substituted.

The term “C₁₋₆alkyl,” as used herein, means a straight, branched chain,or cyclic (in this case, it would also be known as “cycloalkyl”)hydrocarbon containing from 1-6 carbon atoms.

The term “C₁₋₃alkyl,” as used herein, means a straight or branched chainhydrocarbon containing from 1-3 carbon atoms.

The term “alkenyl,” as used herein, means a straight, branched chain, orcyclic (in which case, it would also be known as a “cycloalkenyl”)hydrocarbon containing from 2-10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens. Insome embodiments, depending on the structure, an alkenyl group is amonoradical or a diradical (e.g., an alkenylene group). In someembodiments, alkenyl groups are optionally substituted. Examples ofalkenyl include, but are not limited to, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, and2-methyl-1-heptenyl. In certain embodiments, alkenyl groups areoptionally substituted.

The term “C₂₋₆ alkenyl,” as used herein, means a straight, branchedchain, or cyclic (in this case, it would also be known as “cycloalkyl”)hydrocarbon containing from 2-6 carbon atoms and at least onecarbon-carbon double bond formed by the removal of two hydrogens.

The term “alkoxy,” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Examples of alkoxy include, but are not limited to, methoxy, ethoxy,propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

An “amino acid” (or AA) or amino acid residue include but are notlimited to the 20 naturally occurring amino acids commonly designated bythree letter symbols and also includes 4-hydroxyproline, hydroxyysine,demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, homocysteine, homoserine, omithine andmethionine sulfone. The amino acid residue of the present applicationalso include the corresponding N-methyl amino acids, such as—N(CH₃)CH₂C(O)O—, —NHC(O)CH₂CH₂CH(NHCH₃)C(O)O—, etc. The amino acids,dipeptides, tripeptides, oligomers and polypeptides designated as-(AA)_(r)- of the present application may include the correspondingnon-N-alkylated amino acids and peptides (such as non-N-methylated aminoacids in the peptides), as well as a mixture of the non-N-alkylatedamino acids and the N-alkylated amino acids of the peptides.

An “antibody-drug conjugate” or “ADC” is an antibody that is conjugatedto one or more cytotoxins, through one or more linkers. An antibody-drugconjugate (ADC) may be of the formula A-L-CTX, wherein A is an antibody,L is a linker, and CTX is a cytotoxin.

In the context of a polypeptide, the term “analog” as used herein refersto a polypeptide that possesses a similar or identical function as aC10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or ananti-C10orf54 antibody but does not necessarily comprise a similar oridentical amino acid sequence of a C10orf54 polypeptide, a fragment of aC10orf54 polypeptide, or an anti-C10orf54 antibody, or possess a similaror identical structure of a C10orf54 polypeptide, a fragment of aC10orf54 polypeptide, or an anti-C10orf54 antibody. A polypeptide thathas a similar amino acid sequence refers to a polypeptide that satisfiesat least one of the following: (a) a polypeptide having an amino acidsequence that is at least 30%, at least 35%, at least 40%, at least 45%,at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, or atleast 99% identical to the amino acid sequence of a C10orf54 polypeptide(e.g., SEQ ID NO:1079), a fragment of a C10orf54 polypeptide, or ananti-C10orf54 antibody described herein; (b) a polypeptide encoded by anucleotide sequence that hybridizes under stringent conditions to anucleotide sequence encoding a C10orf54 polypeptide, a fragment of aC10orf54 polypeptide, or an anti-C10orf54 antibody (or VH or VL regionthereof) described herein of at least 5 amino acid residues, at least 10amino acid residues, at least 15 amino acid residues, at least 20 aminoacid residues, at least 25 amino acid residues, at least 40 amino acidresidues, at least 50 amino acid residues, at least 60 amino residues,at least 70 amino acid residues, at least 80 amino acid residues, atleast 90 amino acid residues, at least 100 amino acid residues, at least125 amino acid residues, or at least 150 amino acid residues (see, e.g.,Sambrook et al. (2001) Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Maniatis etal. (1982) Molecular Cloning: A Laboratory Manual, Cold Spring HarborPress, Cold Spring Harbor, N.Y.); and (c) a polypeptide encoded by anucleotide sequence that is at least 30%, at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, or at least 99% identical to the nucleotide sequence encodinga C10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or ananti-C10orf54 antibody (or VH or VL region thereof) described herein. Apolypeptide with similar structure to a C10orf54 polypeptide, a fragmentof a C10orf54 polypeptide, or an anti-C10orf54 antibody described hereinrefers to a polypeptide that has a similar secondary, tertiary orquaternary structure of a C10orf54 polypeptide, a fragment of aC10orf54, or a C10orf54 antibody described herein. The structure of apolypeptide can determined by methods known to those skilled in the art,including but not limited to, X-ray crystallography, nuclear magneticresonance, and crystallographic electron microscopy.

As used herein, an “antagonist” or “inhibitor” of C10orf54 refers to amolecule that is capable of inhibiting or otherwise decreasing one ormore of the biological activities of C10orf54, such as in a cellexpressing C10orf54 or in a cell expressing a C10orf54 ligand, such as aC10orf54 receptor. In some embodiments, an antagonist of C10orf54 (e.g.,an antagonistic antibody provided herein) may, for example, act byinhibiting or otherwise decreasing the activation and/or cell signalingpathways of the cell expressing a C10orf54 or a C10orf54 receptor,thereby inhibiting a C10orf54-mediated biological activity of the cellthe relative to the C10orf54-mediated biological activity in the absenceof antagonist. In certain embodiments the antibodies provided herein areantagonistic anti-C10orf54 antibodies.

The terms “antibody” and “immunoglobulin” or “Ig” are usedinterchangeably herein, and are intended to include a polypeptideproduct of B cells within the immunoglobulin class of polypeptides thatis able to bind to a specific molecular antigen and is composed of twoidentical pairs of polypeptide chains, wherein each pair has one heavychain (about 50-70 kDa) and one light chain (about 25 kDa) and eachamino-terminal portion of each chain includes a variable region of about100 to about 130 or more amino acids and each carboxy-terminal portionof each chain includes a constant region (See, Borrebaeck (ed.) (1995)Antibody Engineering, Second Ed., Oxford University Press; Kuby (1997)Immunology, Third Ed., W.H. Freeman and Company, New York). In specificembodiments, the specific molecular antigen can be bound by an antibodyprovided herein includes the target C10orf54 polypeptide, fragment orepitope.

Antibodies also include, but are not limited to, synthetic antibodies,monoclonal antibodies, recombinantly produced antibodies, multispecificantibodies (including bi-specific antibodies), human antibodies,humanized antibodies, camelized antibodies, chimeric antibodies,intrabodies, anti-idiotypic (anti-Id) antibodies, and functionalfragments of any of the above, which refers a portion of an antibodyheavy or light chain polypeptide that retains some or all of the bindingactivity of the antibody from which the fragment was derived.Non-limiting examples of functional fragments include single-chain Fvs(scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments,F(ab′) fragments, F(ab)₂ fragments, F(ab′)₂ fragments, disulfide-linkedFvs (sdFv), Fd fragments, Fv fragments, diabody, triabody, tetrabody andminibody. In particular, antibodies provided herein includeimmunoglobulin molecules and immunologically active portions ofimmunoglobulin molecules, e.g., antigen binding domains or moleculesthat contain an antigen-binding site that binds to a C10orf54 antigen(e.g., one or more complementarity determining regions (CDRs) of ananti-C10orf54 antibody). Such antibody fragments can be found describedin, for example, Harlow and Lane, Antibodies: A Laboratory Manual, ColdSpring Harbor Laboratory, New York (1989); Myers (ed.), Molec. Biologyand Biotechnology: A Comprehensive Desk Reference, New York: VCHPublisher, Inc.; Huston et al., Cell Biophysics, 22:189-224 (1993);Plückthun and Skerra, Meth. Enzymol., 178:497-515 (1989) and in Day, E.D., Advanced Immunochemistry, Second Ed., Wiley-Liss, Inc., New York,N.Y. (1990). The antibodies provided herein can be of any type (e.g.,IgG, IgE, IgM, IgD, IgA and IgY), any class (e.g., IgG1, IgG2, IgG3,IgG4, IgA1 and IgA2), or any subclass (e.g., IgG2a and IgG2b) ofimmunoglobulin molecule. An anti-C10orf54 antibodies provided herein canbe agonistic antibodies or antagonistic antibodies.

The terms “antibodies that specifically bind to C10orf54,” “antibodiesthat specifically bind to a C10orf54 epitope,” “anti-C10orf54antibodies” and analogous terms are also used interchangeably herein andrefer to antibodies that specifically bind to a C10orf54 polypeptide,such as a C10orf54 antigen or epitope. Such antibodies include humanizedantibodies. An antibody that specifically binds to a C10orf54 antigenmay be cross-reactive with related antigens. In certain embodiments, anantibody that specifically binds to a C10orf54 antigen does notcross-react with other antigens. An antibody that specifically binds toa C10orf54 antigen can be identified, for example, by immunoassays,BIAcore, or other techniques known to those of skill in the art. Anantibody binds specifically to a C10orf54 antigen when it binds to aC10orf54 antigen with higher affinity than to any cross-reactive antigenas determined using experimental techniques, such as radioimmunoassays(RIA) and enzyme-linked immunosorbent assays (ELISAs). Typically aspecific or selective reaction will be at least twice background signalor noise and more typically more than 10 times background. See, e.g.,Paul, ed., 1989, Fundamental Immunology Second Edition, Raven Press, NewYork at pages 332-336 for a discussion regarding antibody specificity.In certain embodiments, an antibody “which binds” an antigen of interestis one that binds the antigen with sufficient affinity such that theantibody is useful as a diagnostic and/or therapeutic agent in targetinga cell or tissue expressing the antigen, and does not significantlycross-react with other proteins. In such embodiments, the extent ofbinding of the antibody to a “non-target” protein will be less thanabout 10% of the binding of the antibody to its particular targetprotein as determined by fluorescence activated cell sorting (FACS)analysis or radioimmunoprecipitation (RIA). With regard to the bindingof an antibody to a target molecule, the term “specific binding” or“specifically binds to” or is “specific for” a particular polypeptide oran epitope on a particular polypeptide target means binding that ismeasurably different from a non-specific interaction. Specific bindingcan be measured, for example, by determining binding of a moleculecompared to binding of a control molecule, which generally is a moleculeof similar structure that does not have binding activity. For example,specific binding can be determined by competition with a controlmolecule that is similar to the target, for example, an excess ofnon-labeled target. In this case, specific binding is indicated if thebinding of the labeled target to a probe is competitively inhibited byexcess unlabeled target. The term “specific binding” or “specificallybinds to” or is “specific for” a particular polypeptide or an epitope ona particular polypeptide target as used herein can be exhibited, forexample, by a molecule having a Kd for the target of at least about 10⁻⁴M, alternatively at least about 10⁻⁵ M, alternatively at least about10⁻⁶ M, alternatively at least about 10⁻⁷ M, alternatively at leastabout 10⁻⁸ M, alternatively at least about 10⁻⁹ M, alternatively atleast about 10⁻¹⁰ M, alternatively at least about 10⁻¹¹ M, alternativelyat least about 10⁻¹² M, or greater. In one embodiment, the term“specific binding” refers to binding where a molecule binds to aparticular polypeptide or epitope on a particular polypeptide withoutsubstantially binding to any other polypeptide or polypeptide epitope.In certain embodiments, an antibody that binds to C10orf54 has adissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM.In certain embodiments, anti-C10orf54 antibody binds to an epitope ofC10orf54 that is conserved among C10orf54 from different species.

An “anti-c10orf54 antibody” or “an antibody that binds to C10orf54”refers to an antibody that is capable of binding C10orf54, including,for example, an antibody, with sufficient affinity such that theantibody is useful as a diagnostic and/or therapeutic agent in targetingC10orf54. Such antibodies include humanized antibodies. Preferably, theextent of binding of an anti-C10orf54 antibody to an unrelated,non-C10orf54 protein is less than about 10% of the binding of theantibody to C10orf54 as measured, e.g., by fluorescence activated cellsorting (FACS) analysis or a radioimmunoassay (RIA). An antibody that“specifically binds to” or is “specific for” C10orf54 is defined asabove. In certain embodiments, an antibody that binds to C10orf54 has adissociation constant (Kd) of <1 μM, <100 nM, <10 nM, <1 nM, or <0.1 nM.In certain embodiments, anti-C10orf54 antibody binds to an epitope ofC10orf54 that is conserved among C10orf54 from different species. An“antigen” is a predetermined antigen to which an antibody canselectively bind.

The target antigen may be a polypeptide, carbohydrate, nucleic acid,lipid, hapten or other naturally occurring or synthetic compound. Inspecific embodiments, the target antigen is a polypeptide.

The term “antigen binding fragment,” “antigen binding domain,” “antigenbinding region,” and similar terms refer to that portion of an antibodywhich comprises the amino acid residues that interact with an antigenand confer on the binding agent its specificity and affinity for theantigen (e.g., the complementarity determining regions (CDRs)).

The terms “binds” or “binding” as used herein refer to an interactionbetween molecules to form a complex. Interactions can be, for example,non-covalent interactions including hydrogen bonds, ionic bonds,hydrophobic interactions, and/or van der Waals interactions. A complexcan also include the binding of two or more molecules held together bycovalent or non-covalent bonds, interactions or forces. The strength ofthe total non-covalent interactions between a single antigen-bindingsite on an antibody and a single epitope of a target molecule, such asC10orf54, is the affinity of the antibody or functional fragment forthat epitope. The ratio of association (k₁) to dissociation (k⁻¹) of anantibody to a monovalent antigen (k₁/k⁻¹) is the association constant K,which is a measure of affinity. The value of K varies for differentcomplexes of antibody and antigen and depends on both k₁ and k⁻¹. Theassociation constant K for an antibody provided herein can be determinedusing any method provided herein or any other method well known to thoseskilled in the art. The affinity at one binding site does not alwaysreflect the true strength of the interaction between an antibody and anantigen. When complex antigens containing multiple, repeating antigenicdeterminants, such as a polyvalent C10orf54, come in contact withantibodies containing multiple binding sites, the interaction ofantibody with antigen at one site will increase the probability of areaction at a second site. The strength of such multiple interactionsbetween a multivalent antibody and antigen is called the avidity. Theavidity of an antibody can be a better measure of its binding capacitythan is the affinity of its individual binding sites. For example, highavidity can compensate for low affinity as is sometimes found forpentameric IgM antibodies, which can have a lower affinity than IgG, butthe high avidity of IgM, resulting from its multivalence, enables it tobind antigen effectively.

The term “C10orf54” or “C10orf54 polypeptide” and similar terms refersto the polypeptide (“polypeptide,” “peptide” and “protein” are usedinterchangeably herein) encoded by the human Chromosome 10 Open ReadingFrame 54 (C10orf54) gene, which is also known in the art as B7-H5,platelet receptor Gi24, GI124, Stress Induced Secreted Protein1, SISP1,and PP2135, comprising the amino acid sequence of:

(SEQ ID NO: 1079)   1mgvptaleag swrwgsllfa lflaaslgpv aafkvatpys lyvcpegqnv tltcrllgpv  61dkghdvtfyk twyrssrgev qtcserrpir nltfqdlhlh hgghqaants hdlaqrhgle 121sasdhhgnfs itmrnltlld sglycclvve irhhhsehrv hgamelqvqt gkdapsncvv 181ypsssqdsen itaaalatga civgilclpl illlvykqrq aasnrraqel vrmdsniqgi 241enpgfeaspp aqgipeakvr hplsyvaqrq psesgrhlls epstplsppg pgdvffpsld 301pvpdspnfev Iand related polypeptides, including SNP variants thereof. The C10orf54polypeptide has been shown to or is predicted to comprise severaldistinct regions within the amino acid sequence including: a signalsequence (residues 1-32; see Zhang et al., Protein Sci. 13:2819-2824(2004)); an immunoglobulin domain—IgV-like (residues 33-162); and atransmembrane region (residues 195-215). The mature C10orf54 proteinincludes amino acid residues 33-311 of SEQ ID NO: 1079. Theextracellular domain of the C10orf54 protein includes amino acidresidues 33-194 of SEQ ID NO: 1079. Related polypeptides include allelicvariants (e.g., SNP variants); splice variants; fragments; derivatives;substitution, deletion, and insertion variants; fusion polypeptides; andinterspecies homologs, preferably, which retain C10orf54 activity and/orare sufficient to generate an anti-C10orf54 immune response. As thoseskilled in the art will appreciate, an anti-C10orf54 antibody providedherein can bind to a C10orf54 polypeptide, polypeptide fragment,antigen, and/or epitope, as an epitope is part of the larger antigen,which is part of the larger polypeptide fragment, which, in turn, ispart of the larger polypeptide. C10orf54 can exist in a native ordenatured form. The C10ORF54 polypeptides described herein may beisolated from a variety of sources, such as from human tissue types orfrom another source, or prepared by recombinant or synthetic methods. A“native sequence C10ORF54 polypeptide” comprises a polypeptide havingthe same amino acid sequence as the corresponding C10ORF54 polypeptidederived from nature. Such native sequence C10ORF54 polypeptides can beisolated from nature or can be produced by recombinant or syntheticmeans. The term “native sequence C10ORF54 polypeptide” specificallyencompasses naturally-occurring truncated or secreted forms of thespecific C10ORF54 polypeptide (e.g., an extracellular domain sequence),naturally-occurring variant forms (e.g., alternatively spliced forms)and naturally-occurring allelic variants of the polypeptide.

A cDNA nucleic acid sequence encoding the C10orf54 polypeptidecomprises:

(SEQ ID NO: 1080)   1atgggcgtcc ccacggccct ggaggccggc agctggcgct ggggatccct gctcttcgct  61ctcttcctgg ctgcgtccct aggtccggtg gcagccttca aggtcgccac gccgtattcc 121ctgtatgtct gtcccgaggg gcagaacgtc accctcacct gcaggctctt gggccctgtg 181gacaaagggc acgatgtgac cttctacaag acgtggtacc gcagctcgag gggcgaggtg 241cagacctgct cagagcgccg gaccatccgc aacctcacgt tccaggacct tcacctgcac 301catggaggcc accaggctgc caacaccagc cacgacctgg ctcagcgcca cgggctggag 361tcggcctccg accaccatgg caacttctcc atcaccatgc gcaacctgac cctgctggat 421agcggcctct actgctgcct ggtggtggag atcaggcacc accactcgga gcacagggtc 481catggtgcca tggagctgca ggtgcagaca ggcaaagatg caccatccaa ctgtgtggtg 541tacccatcct cctcccagga tagtgaaaac atcacggctg cagccctcmc tacgggtgcc 601tgcatcgtag gaatcctctg cctccccgtc atcctgctcc tggtctacaa gcaaaggcag 661gcagcctcca accgccgtgc ccaggagctg gtgcggatgg acagcaacat tcaagggatt 721gaaaaccccg gctttgaagc ctcaccacct gcccagggga tacccgaggc caaagtcagg 781caccccctgt cctatgtggc ccagcggcag ccttctgagt ctgggcggca tctgctttcg 841gagcccagca cccccctgtc tcctccaggc cccggagacg tcttcttccc atccctggac 901cctgtccctg actctccaaa ctttgaggtc atctag

Orthologs to the C10orf54 polypeptide are also well known in the art.For example, the mouse ortholog to the C10orf54 polypeptide is V-regionImmunoglobulin-containing Suppressor of T cell Activation (VISTA) (alsoknown as PD-L3, PD-1H, PD-XL, Pro1412 and UNQ730), which sharesapproximately 70% sequence identity to the human polypeptide. Orthologsof C10orf54 can also be found in additional organisms includingchimpanzee, cow, rat and zebrafish.

A “C10orf54-expressing cell,” “a cell having expression of C10orf54” ora grammatical equivalent thereof refers to a cell that expressesendogenous or transfected C10orf54 on the cell surface. C10orf54expressing cells include a C10orf54-berring tumor cells, regulatorytumor cells (e.g., CD4⁺ Foxp3⁺ regulatory T cells), myeloid-derivedsuppressor cells (e.g., CD11b⁺ or CD11b^(high) myeloid-derivedsuppressor cells) and/or suppressive dendritic cells (e.g., CD11b⁺ orCD11b^(high) dendritic cells). A cell expressing C10orf54 producessufficient levels of C10orf54 on its surface, such that an anti-C10orf54antibody can bind thereto. In some aspect, such binding may have atherapeutic effect with respect to the cancer. A cell that“overexpresses” C10orf54 is one that has significantly higher levels ofC10orf54 at the cell surface thereof, compared to a cell of the sametissue type that is known to express C10orf54. Such overexpression maybe caused by gene amplification or by increased transcription ortranslation. C10orf54 overexpression may be determined in a diagnosticor prognostic assay by evaluating increased levels of the C10orf54protein present on the surface of a cell (e.g. via animmunohistochemistry assay; FACS analysis). Alternatively, oradditionally, one may measure levels of C10orf54-encoding nucleic acidor mRNA in the cell, e.g. via fluorescent in situ hybridization; (FISH;see W098/45479 published October, 1998), Southern blotting, Northernblotting, or polymerase chain reaction (PCR) techniques, such as realtime quantitative PCR (RT-PCR). Aside from the above assays, various invivo assays are available to the skilled practitioner. For example, onemay expose cells within the body of the patient to an antibody which isoptionally labeled with a detectable agent, and binding of the antibodyto cells in the patient can be evaluated, e.g. by external scanning forradioactivity or by analyzing a biopsy taken from a patient previouslyexposed to the antibody. A C10orf54-expressing tumor cell includes, butis not limited to, acute myeloid leukemia (AML) tumor cells.

A “C10orf54-mediated disease,” “C10orf54-mediated disorder” and“C10orf54-mediated condition” are used interchangeably and refer to anydisease, disorder or condition that is completely or partially caused byor is the result of C10orf54. Such diseases, disorders or conditionsinclude those caused by or otherwise associated with C10orf54, includingby or associated with C10orf54-expressing cells (e.g., tumor cells,myeloid-derived suppressor cells (MDSC), suppressive dendritic cells(suppressive DC), and/or regulatory T cells (T regs)). In certainembodiments, C10orf54 is aberrantly (e.g., highly) expressed on thesurface of a cell. In some embodiments, C10orf54 may be aberrantlyupregulated on a particular cell type. In other embodiments, normal,aberrant or excessive cell signaling is caused by binding of C10orf54 toa C10orf54 ligand, which can bind or otherwise interact with C10orf54.

The terms “cell proliferative disorder” and “proliferative disorder”refer to disorders that are associated with some degree of abnormal cellproliferation. In one embodiment, the cell proliferative disorder is atumor or cancer. “Tumor,” as used herein, refers to all neoplastic cellgrowth and proliferation, whether malignant or benign, and allpre-cancerous and cancerous cells and tissues. The terms “cancer,”“cancerous,” “cell proliferative disorder,” “proliferative disorder” and“tumor” are not mutually exclusive as referred to herein. The terms“cancer” and “cancerous” refer to or describe the physiologicalcondition in mammals that is typically characterized by unregulated cellgrowth. Examples of cancer include, but are not limited to, carcinoma,lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include squamous cell cancer (e.g.epithelial squamous cell cancer), lung cancer including small-cell lungcancer, non-small cell lung cancer, adenocarcinoma of the lung andsquamous carcinoma of the lung, cancer of the peritoneum, hepatocellularcancer, gastric or stomach cancer including gastrointestinal cancer,pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, oralcancer, liver cancer, bladder cancer, cancer of the urinary tract,hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer,endometrial or uterine carcinoma, salivary gland carcinoma, kidney orrenal cancer, prostate cancer, vulval cancer, thyroid cancer, hepaticcarcinoma, anal carcinoma, penile carcinoma, melanoma, multiple myelomaand B-cell lymphoma, brain cancer, as well as head and neck cancer, andassociated metastases.

The term “carrier” refers to a diluent, adjuvant (e.g., Freund'sadjuvant (complete and incomplete)), excipient, or vehicle with whichthe therapeutic is administered. Such pharmaceutical carriers can besterile liquids, such as water and oils, including those of petroleum,animal, vegetable or synthetic origin, such as peanut oil, soybean oil,mineral oil, sesame oil and the like. Water is a exemplary carrier whenthe pharmaceutical composition is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid carriers, particularly for injectable solutions.Suitable pharmaceutical excipients include starch, glucose, lactose,sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water, ethanol and the like. The composition, ifdesired, can also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents. These compositions can take the form ofsolutions, suspensions, emulsion, tablets, pills, capsules, powders,sustained-release formulations and the like. Oral formulation caninclude standard carriers such as pharmaceutical grades of mannitol,lactose, starch, magnesium stearate, sodium saccharine, cellulose,magnesium carbonate, etc. Examples of suitable pharmaceutical carriersare described in Remington's Pharmaceutical Sciences (1990) MackPublishing Co., Easton, Pa. Such compositions will contain aprophylactically or therapeutically effective amount of the antibody,e.g., in isolated or purified form, together with a suitable amount ofcarrier so as to provide the form for proper administration to thepatient. The formulation should suit the mode of administration. Theterm “chemical group,” as used herein, refers to two or more atoms boundtogether as a single unit and forming part of a molecule.

A “chemotherapeutic agent” is a chemical agent (e.g., compound or drug)useful in the treatment of cancer, regardless of mechanism of action.Chemotherapeutic agents include compounds used in targeted therapy andconventional chemotherapy. Examples of chemotherapeutic agents include,but are not limited to, alkylating agents such as thiotepa and CYTOXAN®cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethiylenethiophosphoramide and trimethylolomelamine; acetogenins(especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol(dronabinol, ARINOL®); beta-lapachone; lapachol; colchicines; betulinicacid; a camptothecin (including the synthetic analogue topotecan(HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin,scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); podophyllotoxin; podophyllinic acid; teniposide;cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogues, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlomaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine;antibiotics such as the enediyne antibiotics (e.g., calicheamicin,especially calicheamicin gammal I and calicheamicin omega II (see, e.g.,Agnew, Chem Intl. Ed. Engl. 33:183-186 (1994)); dynemicin, includingdynemicin A; an esperamicin; as well as neocarzinostatin chromophore andrelated chromoprotein enediyne antiobiotic chromophores),aclacinomysins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis,dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,ADRIAMYCIN®, doxorubicin (including morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin anddeoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin,mitomycins such as mitomycin C, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS NaturalProducts, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium;tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine;trichothecenes (especially T-2 toxin, verracurin A, roridin A andanguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); thiotepa; taxoids, e.g., TAXOL® paclitaxel(Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE™Cremophor-free, albumin-engineered nanoparticle formulation ofpaclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), andTAXOTERE® doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil;gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine(VELBAN®); platinum; etoposide (VP-16); ifosfamide; mitoxantrone;vincristine (ONCOVIN®); oxaliplatin; leucovovin; vinorelbine(NAVELBINE®); novantrone; edatrexate; daunomycin; aminopterin;ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylomithine(DMFO); retinoids such as retinoic acid; capecitabine (XELODA®);pharmaceutically acceptable salts, acids or derivatives of any of theabove; as well as combinations of two or more of the above such as CHOP,an abbreviation for a combined therapy of cyclophosphamide, doxorubicin,vincristine, and prednisolone, and FOLFOX, an abbreviation for atreatment regimen with oxaliplatin (ELOXATIN™) combined with 5-FU andleucovovin. Additional chemotherapeutic agents include cytotoxic agentsuseful as antibody drug conjugates, such as maytansinoids (DM1 and DM4,for example) and auristatins (MMAE and MMAF, for example).

Also included in the definition of chemotherapeutic agent are: (i)anti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens and selective estrogen receptor modulators(SERMs), including, for example, tamoxifen (including NOLVADEX®tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen,trioxifene, keoxifene, LY 117018, onapristone, and FARESTON® (toremifinecitrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase,which regulates estrogen production in the adrenal glands, such as, forexample, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrolacetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISor® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide,nilutamide, bicalutamide, leuprolide, and goserelin; as well astroxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) proteinkinase inhibitors such as ME inhibitors (WO 2007/044515); (v) lipidkinase inhibitors; (vi) antisense oligonucleotides, particularly thosewhich inhibit expression of genes in signaling pathways implicated inaberrant cell proliferation, for example, PKC-alpha, Raf and H-Ras, suchas oblimersen (GENASENSE®, Genta Inc.); (vii) ribozymes such as VEGFexpression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors;(viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®,LEUVECTIN®, and VAX1D®; PROLEUKIN® rIL-2; topoisomerase 1 inhibitorssuch as LURTOTECAN®; ABARELIX® rmRH; (ix) anti-angiogenic agents such asbevacizumab (AVASTIN®, Genentech); and pharmaceutically acceptablesalts, acids and derivatives of any of the above.

The antibodies provided herein can include “chimeric” antibodies inwhich a portion of the heavy and/or light chain is identical with orhomologous to corresponding sequences in antibodies derived from aparticular species or belonging to a particular antibody class orsubclass, while the remainder of the chain(s) is identical with orhomologous to corresponding sequences in antibodies derived from anotherspecies or belonging to another antibody class or subclass, as well asfragments of such antibodies, so long as they exhibit the desiredbiological activity (see U.S. Pat. No. 4,816,567; and Morrison et al.,Proc. Nat!. Acad. Sci. USA, 81:6851-6855 (1984)).

As used herein, the term “composition” is intended to encompass aproduct containing the specified ingredients (e.g., an antibody providedherein) in, optionally, the specified amounts, as well as any productwhich results, directly or indirectly, from combination of the specifiedingredients in, optionally, the specified amounts.

A “CDR” refers to one of three hypervariable regions (H1, H2 or H3)within the non-framework region of the immunoglobulin (Ig or antibody)VH β-sheet framework, or one of three hypervariable regions (L1, L2 orL3) within the non-framework region of the antibody VL β-sheetframework. Accordingly, CDRs are variable region sequences interspersedwithin the framework region sequences. CDR regions are well known tothose skilled in the art and have been defined by, for example, Kabat asthe regions of most hypervariability within the antibody variable (V)domains (Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat, Adv.Prot. Chem. 32:1-75 (1978)). CDR region sequences also have been definedstructurally by Chothia as those residues that are not part of theconserved β-sheet framework, and thus are able to adapt differentconformations (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). Bothterminologies are well recognized in the art. CDR region sequences havealso been defined by AbM, Contact and IMGT. CDR region sequences areillustrated in FIGS. 16A and 16B. The positions of CDRs within acanonical antibody variable domain have been determined by comparison ofnumerous structures (Al-Lazikani et al., J. Mol. Biol. 273:927-948(1997); Morea et al., Methods 20:267-279 (2000)). Because the number ofresidues within a hypervariable region varies in different antibodies,additional residues relative to the canonical positions areconventionally numbered with a, b, c and so forth next to the residuenumber in the canonical variable domain numbering scheme (Al-Lazikani etal., supra (1997)). Such nomenclature is similarly well known to thoseskilled in the art.

The term “hypervariable region”, “HVR”, or “HV”, when used herein refersto the regions of an antibody variable domain that are hypervariable insequence and/or form structurally defined loops. Generally, antibodiescomprise six hypervariable regions; three in the VH (H 1, H2, H3), andthree in the VL (LI, L2, L3). A number of hypervariable regiondelineations are in use and are encompassed herein. The Kabat CDRs arebased on sequence variability and are the most commonly used (Kabateta/, Sequences of Proteins of Immunological Interest, 5th Ed. PublicHealth Service, National Institutes of Health, Bethesda, Md. (1991)).Chothia refers instead to the location of the structural loops (Chothiaand Lesk J Mol. Bioi. 196:901-917 (1987)). The end of the Chothia CDR-HIloop when numbered using the Kabat numbering convention varies betweenH32 and H34 depending on the length of the loop (this is because theKabat numbering scheme places the insertions at H35A and H35B; ifneither 35A nor 35B is present, the loop ends at 32; if only 35A ispresent, the loop ends at 33; if both 35A and 35B are present, the loopends at 34). The AbM hypervariable regions represent a compromisebetween the Kabat CDRs and Chothia structural loops, and are used byOxford Molecular's AbM antibody modeling software. The “contact”hypervariable regions are based on an analysis of the available complexcrystal structures. The residues from each of these hypervariableregions are noted below.

Recently, a universal numbering system has been developed and widelyadopted, ImMunoGeneTics (IMGT) Information System® (Lafranc et al., Dev.Comp. Immunol. 27(1):55-77 (2003)). IMGT is an integrated informationsystem specializing in immunoglobulins (IG), T cell receptors (TR) andmajor histocompatibility complex (MHC) of human and other vertebrates.Herein, the CDRs are referred to in terms of both the amino acidsequence and the location within the light or heavy chain. As the“location” of the CDRs within the structure of the immunoglobulinvariable domain is conserved between species and present in structurescalled loops, by using numbering systems that align variable domainsequences according to structural features, CDR and framework residuesand are readily identified. This information can be used in grafting andreplacement of CDR residues from immunoglobulins of one species into anacceptor framework from, typically, a human antibody. Correspondencebetween the Kabat numbering and the IMGT unique numbering system is alsowell known to one skilled in the art (e.g. Lefranc et al., supra) and isalso illustrated in FIGS. 16A and 16B. An Exemplary system, shownherein, combines Kabat and Chothia.

TABLE 1 CDR Definitions Exemplary (Kabat + Chothia) IMGT Kabat AbMChothia Contact V_(H) CDR1 26-35 27-38 31-35 26-35 26-32 30-35 V_(H)CDR2 50-65 56-65 50-65 50-58 53-55 47-58 V_(H) CDR3  95-102 105-117 95-102  95-102  96-101  93-101 V_(L) CDR1 24-34 27-38 24-34 24-34 26-3230-36 V_(L) CDR2 50-56 56-65 50-56 50-56 50-52 46-55 V_(L) CDR3 89-97105-117 89-97 89-97 91-96 89-96

Hypervariable regions may comprise “extended hypervariable regions” asfollows: 24-36 or 24-34 (LI), 46-56 or 50-56 (L2) and 89-97 or 89-96(L3) in the VL and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2) and 93-102,94-102, or 95-102 (H3) in the VH. The variable domain residues are 25numbered according to Kabat et al., supra, for each of thesedefinitions. As used herein, the terms “HVR” and “CDR” are usedinterchangeably.

The term “constant region” or “constant domain” refers to a carboxyterminal portion of the light and heavy chain which is not directlyinvolved in binding of the antibody to antigen but exhibits variouseffector function, such as interaction with the Fc receptor. The termsrefer to the portion of an immunoglobulin molecule having a moreconserved amino acid sequence relative to the other portion of theimmunoglobulin, the variable domain, which contains the antigen bindingsite. The constant domain contains the CH1, CH2 and CH3 domains of theheavy chain and the CL domain of the light chain.

The term “cycloalkyl,” as used herein, means a monocyclic or polycyclicradical that contains only carbon and hydrogen, and includes those thatare saturated, partially unsaturated, or fully unsaturated. Cycloalkylgroups include groups having from 3 to ring atoms.

In the context of a polypeptide, the term “derivative” as used hereinrefers to a polypeptide that comprises an amino acid sequence of aC10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or anantibody that binds to a C10orf54 polypeptide which has been altered bythe introduction of amino acid residue substitutions, deletions oradditions. The term “derivative” as used herein also refers to aC10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or anantibody that binds to a C10orf54 polypeptide which has been chemicallymodified, e.g., by the covalent attachment of any type of molecule tothe polypeptide. For example, but not by way of limitation, a C10orf54polypeptide, a fragment of a C10orf54 polypeptide, or a C10orf54antibody may be chemically modified, e.g., by glycosylation,acetylation, pegylation, phosphorylation, amidation, derivatization byknown protecting/blocking groups, proteolytic cleavage, linkage to acellular ligand or other protein, etc. The derivatives are modified in amanner that is different from naturally occurring or starting peptide orpolypeptides, either in the type or location of the molecules attached.Derivatives further include deletion of one or more chemical groupswhich are naturally present on the peptide or polypeptide. A derivativeof a C10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or aC10orf54 antibody may be chemically modified by chemical modificationsusing techniques known to those of skill in the art, including, but notlimited to specific chemical cleavage, acetylation, formulation,metabolic synthesis of tunicamycin, etc. Further, a derivative of aC10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or aC10orf54 antibody may contain one or more non-classical amino acids. Apolypeptide derivative possesses a similar or identical function as aC10orf54 polypeptide, a fragment of a C10orf54 polypeptide, or aC10orf54 antibody described herein.

The term “cytotoxic agent” or “cytotoxin” or “CTX” as used herein refersto a substance that inhibits or prevents the function of cells and/orhas a cytotoxic effect on cells (e.g., causes destruction of cells). Theterm is intended to include alkylating agents, an anthracyclines, acytoskeletal disrupters (taxanes), an epothilones, an histonedeacetylase Inhibitor (HDAC), an inhibitor of Topoisomerase I, anInhibitor of Topoisomerase II, a kinase inhibitor, a monoclonalantibodies, a nucleotide analog, a peptide antibiotic, a platinum-basedagent, a retinoids, a Vinca alkaloid or a derivative thereof, andradioisotope. The term is also intended to include Actinomycin,all-trans retinoic acid, Azacitidine, Azathioprine, Bleomycin,Bortezomib, Carboplatin, Capecitabine, Cisplatin, Chlorambucil,Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel, Doxifluridine,Doxorubicin, Epirubicin, Epothilone, Etoposide, Fluorouracil,Gemcitabine, Hydroxyurea, Idarubicin, Imatinib, Irinotecan,Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone,Oxaliplatin, Paclitaxel, Pemetrexed, Teniposide, Tioguanine, Topotecan,Valrubicin, Vinblastine, Vincristine, Vindesine, and Vinorelbine. Theterm is also intended to include a tubulin stabilizer, a tubulindestabilizer, a DNA alkylator, a DNA minor groove binder, a DNAintercalator, a topoisomerase I inhibitor, a topoisomerase II inhibitor,a gyrase inhibitor, a protein synthesis inhibitor, a proteosomeinhibitor, and an anti-metabolite. The term is also intended to includeActinomycin D, Amonafide, an auristatin, benzophenone, benzothiazole, acalicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin,Colchicine, Combretastatin A4, Dolastatin, Doxorubicin, Elinafide,Emtansine (DM1), Etoposide, KF-12347 (Leinamycin), a maytansinoid,Methotrexate, Mitoxantrone, Nocodazole, Proteosome Inhibitor 1 (PSI 1),Roridin A, T-2 Toxin (trichothecene analog), Taxol, a tubulysin,Velcade®, and Vincristine. Preferred cytotoxins include an auristatin, acalicheamicin, a maytansinoid, and a tubulysin. Other preferredcytotoxins include monomethylauristatin E, monomethylauristatin F,calicheamicin γ, mertansine, tubulysin T3, and tubulysin T4, thestructures for which are provided below:

Other cytotoxic agents including various antitumor or anticancer agentsare known in the art.

The term “detectable probe,” as used herein, refers to a compositionthat provides a detectable signal. The term includes, withoutlimitation, any fluorophore, chromophore, radiolabel, enzyme, antibodyor antibody fragment, and the like, that provide a detectable signal viaits activity.

The term “diagnostic agent” refers to a substance administered to asubject that aids in the diagnosis of a disease. Such substances can beused to reveal, pinpoint, and/or define the localization of a diseasecausing process. In certain embodiments, a diagnostic agent includes asubstance that is conjugated to an antibody provided herein, that whenadministered to a subject or contacted to a sample from a subject aidsin the diagnosis of cancer, tumor formation, or any otherC10orf54-mediated disease.

The term “detectable agent” refers to a substance that can be used toascertain the existence or presence of a desired molecule, such as anantibody provided herein, in a sample or subject. A detectable agent canbe a substance that is capable of being visualized or a substance thatis otherwise able to be determined and/or measured (e.g., byquantitation).

An “effective amount” is an amount sufficient to effect beneficial ordesired results. An effective amount can be administered in one or moreadministrations, applications or dosages. Such delivery is dependent ona number of variables including the time period for which the individualdosage unit is to be used, the bioavailability of the agent, the routeof administration, etc. In some embodiments, effective amount alsorefers to the amount of an antibody provided herein to achieve aspecified result (e.g., inhibition of a C10orf54 biological activity ofa cell, such as modulating T cell activation and/or proliferation). Insome embodiments, this term refers to the amount of a therapy (e.g., anantibody or pharmaceutical composition provided herein) which issufficient to reduce and/or ameliorate the severity and/or duration of agiven disease and/or a symptom related thereto. This term alsoencompasses an amount necessary for the reduction or amelioration of theadvancement or progression of a given disease, reduction or ameliorationof the recurrence, development or onset of a given disease, and/or toimprove or enhance the prophylactic or therapeutic effect(s) of anothertherapy (e.g., a therapy other than anti-C10orf54 antibody providedherein). In some embodiments, the effective amount of an antibody isfrom about 0.1 mg/kg (mg of antibody per kg weight of the subject) toabout 100 mg/kg. In certain embodiments, an effective amount of anantibody provided therein is about 0.1 mg/kg, about 0.5 mg/kg, about 1mg/kg, 3 mg/kg, 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg,about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kgabout 90 mg/kg or about 100 mg/kg (or a range therein).

The term “electrophilic leaving group,” as used herein, refers to aleaving group that accepts an electron pair to make a covalent bond. Ingeneral, electrophiles are susceptible to attack by complementarynucleophiles, including the reduced thiols from the disulfide bond of anantibody.

The term “electrophilic leaving group that reacts selectively withthiols,” as used herein, refers to electrophilic leaving group thatreacts selectively with thiols, over other nucleophiles. In certainembodiments, an electrophilic leaving group that reacts selectively withthiols reacts selectively with the reduced thiols from the disulfidebond of an antibody.

The term “encode” or grammatical equivalents thereof as it is used inreference to nucleic acid molecule refers to a nucleic acid molecule inits native state or when manipulated by methods well known to thoseskilled in the art that can be transcribed to produce mRNA, which isthen translated into a polypeptide and/or a fragment thereof. Theantisense strand is the complement of such a nucleic acid molecule, andthe encoding sequence can be deduced therefrom.

The term “epitope” as used herein refers to a localized region on thesurface of an antigen, such as C10orf54 polypeptide or C10orf54polypeptide fragment, that is capable of being bound to one or moreantigen binding regions of an antibody, and that has antigenic orimmunogenic activity in an animal, such as a mammal (e.g., a human),that is capable of eliciting an immune response. An epitope havingimmunogenic activity is a portion of a polypeptide that elicits anantibody response in an animal. An epitope having antigenic activity isa portion of a polypeptide to which an antibody binds as determined byany method well known in the art, for example, by an immunoassay.Antigenic epitopes need not necessarily be immunogenic. Epitopes usuallyconsist of chemically active surface groupings of molecules such asamino acids or sugar side chains and have specific three dimensionalstructural characteristics as well as specific charge characteristics. Aregion of a polypeptide contributing to an epitope may be contiguousamino acids of the polypeptide or the epitope may come together from twoor more non-contiguous regions of the polypeptide. The epitope may ormay not be a three-dimensional surface feature of the antigen. Incertain embodiments, a C10orf54 epitope is a three-dimensional surfacefeature of a C10orf54 polypeptide. In other embodiments, a C10orf54epitope is linear feature of a C10orf54 polypeptide. Generally anantigen has several or many different epitopes and reacts with manydifferent antibodies.

The term “excipient” as used herein refers to an inert substance whichis commonly used as a diluent, vehicle, preservative, binder, orstabilizing agent, and includes, but not limited to, proteins (e.g.,serum albumin, etc.), amino acids (e.g., aspartic acid, glutamic acid,lysine, arginine, glycine, histidine, etc.), fatty acids andphospholipids (e.g., alkyl sulfonates, caprylate, etc.), surfactants(e.g., SDS, polysorbate, nonionic surfactant, etc.), saccharides (e.g.,sucrose, maltose, trehalose, etc.) and polyols (e.g., mannitol,sorbitol, etc.). See, also, Remington's Pharmaceutical Sciences (1990)Mack Publishing Co., Easton, Pa., which is hereby incorporated byreference in its entirety.

In the context of a peptide or polypeptide, the term “fragment” as usedherein refers to a peptide or polypeptide that comprises less than thefull length amino acid sequence. Such a fragment may arise, for example,from a truncation at the amino terminus, a truncation at the carboxyterminus, and/or an internal deletion of a residue(s) from the aminoacid sequence. Fragments may, for example, result from alternative RNAsplicing or from in vivo protease activity. In certain embodiments,C10orf54 fragments include polypeptides comprising an amino acidsequence of at least 5 contiguous amino acid residues, at least 10contiguous amino acid residues, at least contiguous amino acid residues,at least 20 contiguous amino acid residues, at least 25 contiguous aminoacid residues, at least 40 contiguous amino acid residues, at least 50contiguous amino acid residues, at least 60 contiguous amino residues,at least 70 contiguous amino acid residues, at least 80 contiguous aminoacid residues, at least 90 contiguous amino acid residues, at leastcontiguous 100 amino acid residues, at least 125 contiguous amino acidresidues, at least 150 contiguous amino acid residues, at least 175contiguous amino acid residues, at least 200 contiguous amino acidresidues, or at least 250 contiguous amino acid residues of the aminoacid sequence of a C10orf54 polypeptide or an antibody that binds to aC10orf54 polypeptide. In a specific embodiment, a fragment of a C10orf54polypeptide or an antibody that binds to a C10orf54 antigen retains atleast 1, at least 2, or at least 3 functions of the polypeptide orantibody.

The term “framework” or “FR” residues are those variable domain residuesflanking the CDRs. FR residues are present, e.g., in chimeric,humanized, human, domain antibodies, diabodies, linear antibodies, andbispecific antibodies. FR residues are those variable domain residuesother than the hypervariable region residues herein defined.

A “functional fragment” of an antibody will exhibit at least one if notsome or all of the biological functions attributed to the intactantibody, the function comprising at least specific binding to thetarget antigen.

The term “fusion protein” as used herein refers to a polypeptide thatcomprises an amino acid sequence of an antibody and an amino acidsequence of a heterologous polypeptide or protein (e.g., a polypeptideor protein not normally a part of the antibody (e.g., anon-anti-C10orf54 antigen antibody)). The term “fusion” when used inrelation to C10orf54 or to an anti-C10orf54 antibody refers to thejoining of a peptide or polypeptide, or fragment, variant and/orderivative thereof, with a heterologous peptide or polypeptide. Incertain embodiments, the fusion protein retains the biological activityof the C10orf54 or anti-C10orf54 antibody. In certain embodiments, thefusion protein comprises a C10orf54 antibody VH domain, VL domain, VHCDR (one, two or three VH CDRs), and/or VL CDR (one, two or three VLCDRs), wherein the fusion protein binds to a C10orf54 epitope.

The term “heavy chain” when used in reference to an antibody refers to apolypeptide chain of about 50-70 kDa, wherein the amino-terminal portionincludes a variable region of about 120 to 130 or more amino acids and acarboxy-terminal portion that includes a constant region. The constantregion can be one of five distinct types, referred to as alpha (α),delta (δ), epsilon (ε), gamma (γ) and mu (μ), based on the amino acidsequence of the heavy chain constant region. The distinct heavy chainsdiffer in size: α, δ and γ contain approximately 450 amino acids, whileμ and ε contain approximately 550 amino acids. When combined with alight chain, these distinct types of heavy chains give rise to five wellknown classes of antibodies, IgA, IgD, IgE, IgG and IgM, respectively,including four subclasses of IgG, namely IgG1, IgG2, IgG3 and IgG4. Aheavy chain can be a human heavy chain.

The term “host” as used herein refers to an animal, such as a mammal(e.g., a human).

The term “host cell” as used herein refers to the particular subjectcell transfected with a nucleic acid molecule and the progeny orpotential progeny of such a cell. Progeny of such a cell may not beidentical to the parent cell transfected with the nucleic acid moleculedue to mutations or environmental influences that may occur insucceeding generations or integration of the nucleic acid molecule intothe host cell genome.

“Humanized” forms of nonhuman (e.g., murine) antibodies are chimericantibodies that include human immunoglobulins (recipient antibody) inwhich the native CDR residues are replaced by residues from thecorresponding CDR of a nonhuman species (donor antibody) such as mouse,rat, rabbit or nonhuman primate having the desired specificity,affinity, and capacity. In some instances, one or more FR regionresidues of the human immunoglobulin are replaced by correspondingnonhuman residues. Furthermore, humanized antibodies can compriseresidues that are not found in the recipient antibody or in the donorantibody. These modifications are made to further refine antibodyperformance. A humanized antibody heavy or light chain can comprisesubstantially all of at least one or more variable domains, in which allor substantially all of the CDRs correspond to those of a nonhumanimmunoglobulin and all or substantially all of the FRs are those of ahuman immunoglobulin sequence. In certain embodiments, the humanizedantibody will comprise at least a portion of an immunoglobulin constantregion (Fc), typically that of a human immunoglobulin. For furtherdetails, see, Jones et al., Nature, 321:522-525 (1986); Riechmann etal., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.,2:593-596 (1992); Carter et al., Proc. Natl. Acd. Sci. USA 89:4285-4289(1992); and U.S. Pat. No. 6,800,738 (issued Oct. 5, 2004), U.S. Pat. No.6,719,971 (issued Sep. 27, 2005), U.S. Pat. No. 6,639,055 (issued Oct.28, 2003), U.S. Pat. No. 6,407,213 (issued Jun. 18, 2002), and U.S. Pat.No. 6,054,297 (issued Apr. 25, 2000).

An antibody that “inhibits the growth of and/or kills cells expressingC10orf54” or a “growth inhibitory” or “cytotoxic” antibody is one whichresults in measurable growth inhibition and/or killing of cellsexpressing or overexpressing the appropriate C10orf54 polypeptide. Insome embodiments, such antibodies can inhibit the growth of and/or killcells expressing C10orf54. Such cells include regulatory T cells (e.g.,a CD4+Foxp3+ regulatory T cells), a myeloid-derived suppressor cells(e.g., a CD11b+ or CD1 bhigh myeloid-derived suppressor cells) and/or asuppressive dendritic cells (e.g., a CD11b+ or CD1 bhigh dendriticcells). In a specific embodiment, antibodies inhibit the growth ofand/or kill a cancer cell, a pre-cancerous cell, or a cell comprising atumor. Certain growth inhibitory anti-C10orf54 antibodies inhibit growthof and/or kill C10orf54-expressing cells by greater than 20%, such asfrom about 20% to about 50%, or by greater than 50% (e.g., from about50% to about 100%) as compared to the appropriate control, the controltypically being cells not treated with the antibody being tested. In oneembodiment, growth inhibition and/or killing can be measured at anantibody concentration of about 0.1 to 30 g/ml or about 0.5 nM to 200 nMin cell culture, where the growth inhibition is determined 1-10 daysafter exposure of the tumor cells to the antibody. Growth inhibitionand/or killing of cells in vivo can be determined in various ways suchas is described below. In the context of inhibiting a cancer cell or acell comprising a tumor, the antibody is growth inhibitory or kills invivo if administration of the anti-C10orf54 antibody at about 1 g/kg toabout 100 mg/kg body weight results in reduction in tumor size or tumorcell proliferation within about 5 days to 3 months from the firstadministration of the antibody, such as within about 5 to 30 days.

As used herein, the term “in combination” in the context of theadministration of other therapies refers to the use of more than onetherapy. The use of the term “in combination” does not restrict theorder in which therapies are administered to a subject with aninfection. A first therapy can be administered before (e.g., 1 minute,45 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours,12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks), concurrently,or after (e.g., 1 minute, 45 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks) the administration of a second therapy to a subject which had,has, or is susceptible to a C10orf54-mediated disease. Any additionaltherapy can be administered in any order with the other additionaltherapies. In certain embodiments, the antibodies can be administered incombination with one or more therapies (e.g., therapies that are not theantibodies that are currently administered to prevent, treat, manage,and/or ameliorate a C10orf54-mediated disease. Non-limiting examples oftherapies that can be administered in combination with an antibodyinclude analgesic agents, anesthetic agents, antibiotics, orimmunomodulatory agents or any other agent listed in the U.S.Pharmacopoeia and/or Physician's Desk Reference.

An antibody that “induces cell death” is one that causes a viable cellto become nonviable. The cell is of a cell type that specificallyexpresses or overexpresses a C10orf54 polypeptide. The cell may becancerous or a normal cell of the particular cell type, such as aregulatory T cell. Cell death in vitro may be determined in the absenceof complement and immune effector cells to distinguish cell deathinduced by antibody-dependent cell-mediated cytotoxicity (ADCC) orcomplement dependent cytotoxicity (CDC). Thus, the assay for cell deathmay be performed using heat inactivated serum (e.g., in the absence ofcomplement) and in the absence of immune effector cells. To determinewhether the antibody is able to induce cell death, loss of membraneintegrity as evaluated by uptake of propidium iodide (PI), trypan blue(see Moore et al. Cytotechnology 17:1-11 (1995)). In some embodiments,cell death-inducing antibodies are those which induce PI uptake in thePI uptake assay in C10orf54 expressing cells.

An “isolated” antibody is substantially free of cellular material orother contaminating proteins from the cell or tissue source and/or othercontaminant components from which the antibody is derived, orsubstantially free of chemical precursors or other chemicals whenchemically synthesized. The language “substantially free of cellularmaterial” includes preparations of an antibody in which the antibody isseparated from cellular components of the cells from which it isisolated or recombinantly produced. Thus, an antibody that issubstantially free of cellular material includes preparations ofantibody having less than about 30%, 20%, 10%, or 5% (by dry weight) ofheterologous protein (also referred to herein as a “contaminatingprotein”). In certain embodiments, when the antibody is recombinantlyproduced, it is substantially free of culture medium, e.g., culturemedium represents less than about 20%, 10%, or 5% of the volume of theprotein preparation. In certain embodiments, when the antibody isproduced by chemical synthesis, it is substantially free of chemicalprecursors or other chemicals, e.g., it is separated from chemicalprecursors or other chemicals which are involved in the synthesis of theprotein. Accordingly such preparations of the antibody have less thanabout 30%, 20%, 10%, 5% (by dry weight) of chemical precursors orcompounds other than the antibody of interest. Contaminant componentscan also include, but are not limited to, materials that would interferewith therapeutic uses for the antibody, and may include enzymes,hormones, and other proteinaceous or nonproteinaceous solutes. Incertain embodiments, the antibody will be purified (1) to greater than95% by weight of antibody as determined by the Lowry method (Lowry etal. J. Bio. Chem. 193: 265-275, 1951), such as 99% by weight, (2) to adegree sufficient to obtain at least 15 residues of N-terminal orinternal amino acid sequence by use of a spinning cup sequenator, or (3)to homogeneity by SDS-PAGE under reducing or nonreducing conditionsusing Coomassie blue or, preferably, silver stain. Isolated antibodyincludes the antibody in situ within recombinant cells since at leastone component of the antibody's natural environment will not be present.Ordinarily, however, isolated antibody will be prepared by at least onepurification step. In a specific embodiment, antibodies provided hereinare isolated

An “isolated” nucleic acid molecule is one which is separated from othernucleic acid molecules which are present in the natural source of thenucleic acid molecule. Moreover, an “isolated” nucleic acid molecule,such as a cDNA molecule, can be substantially free of other cellularmaterial, or culture medium when produced by recombinant techniques, orsubstantially free of chemical precursors or other chemicals whenchemically synthesized. In a specific embodiment, a nucleic acidmolecule(s) encoding an antibody provided herein is isolated orpurified.

The term “leaving group,” as used herein, refers to any group thatleaves in the course of a chemical reaction involving the group asdescribed herein and includes but is not limited to halogen, sulfonates(brosylate, mesylate, tosylate triflate etc. . . . ), p-nitrobenzoateand phosphonate groups, for example.

The term “light chain” when used in reference to an antibody refers to apolypeptide chain of about 25 kDa, wherein the amino-terminal portionincludes a variable region of about 100 to about 110 or more amino acidsand a carboxy-terminal portion that includes a constant region. Theapproximate length of a light chain is 211 to 217 amino acids. There aretwo distinct types, referred to as kappa (κ) of lambda (λ) based on theamino acid sequence of the constant domains. Light chain amino acidsequences are well known in the art. A light chain can be a human lightchain.

A “linker” (noted as L or L¹, L² and L³) is a molecule with two reactivetermini, one for conjugation to an antibody or to another linker and theother for conjugation to a cytotoxin. The antibody conjugation reactiveterminus of the linker is typically a site that is capable ofconjugation to the antibody through a cysteine thiol or lysine aminegroup on the antibody, and so is typically a thiol-reactive group suchas a double bond (as in maleimide) or a leaving group such as a chloro,bromo or iodo or an R-sulfanyl group or sulfonyl group, or anamine-reactive group such as a carboxyl group or as defined herein;while the antibody conjugation reactive terminus of the linker istypically a site that is capable of conjugation to the cytotoxin throughformation of an amide bond with a basic amine or carboxyl group on thecytotoxin, and so is typically a carboxyl or basic amine group. In oneembodiment, when the term “linker” is used in describing the linker inconjugated form, one or both of the reactive termini will be absent(such as the leaving group of the thiol-reactive group) or incomplete(such as the being only the carbonyl of the carboxylic acid) because ofthe formation of the bonds between the linker and/or the cytotoxin. Thelinkers disclosed herein may be cleavable under normal physiologicaland/or intracellular conditions, or may remain stable (e.g., uncleavedor non-cleavable) under those same conditions. Examples of cleavablelinkers are linkers which contain dipeptide moieties, where the peptidebond connecting the two peptides has the potential to be selectivelycleaved by lysosomal proteases (e.g., cathepsin-B). Valine-citruline(Val-Cit) is a dipeptide moiety commonly used in cleavable linkers.

As used herein, the terms “manage,” “managing,” and “management” referto the beneficial effects that a subject derives from a therapy (e.g., aprophylactic or therapeutic agent), which does not result in a cure ofthe disease. In certain embodiments, a subject is administered one ormore therapies (e.g., prophylactic or therapeutic agents, such as anantibody provided herein) to “manage” a C10orf54-mediated disease, oneor more symptoms thereof, so as to prevent the progression or worseningof the disease.

The term “monoclonal antibody” refers to an antibody obtained from apopulation of homogenous or substantially homogeneous antibodies, andeach monoclonal antibody will typically recognize a single epitope onthe antigen. In specific embodiments, a “monoclonal antibody,” as usedherein, is an antibody produced by a single hybridoma or other cell,wherein the antibody binds to only a C10orf54 epitope as determined,e.g., by ELISA or other antigen-binding or competitive binding assayknown in the art. The term “monoclonal” is not limited to any particularmethod for making the antibody. For example, monoclonal antibodiesprovided herein may be made by the hybridoma method as described inKohler et al.; Nature, 256:495 (1975) or may be isolated from phagelibraries using the techniques. Other methods for the preparation ofclonal cell lines and of monoclonal antibodies expressed thereby arewell known in the art (see, for example, Chapter 11 in: Short Protocolsin Molecular Biology, (2002) 5th Ed., Ausubel et al., eds., John Wileyand Sons, New York). Other exemplary methods of producing othermonoclonal antibodies are provided in the Examples herein.

The term “native” when used in connection with biological materials suchas nucleic acid molecules, polypeptides, host cells, and the like,refers to those which are found in nature and not manipulated by a humanbeing.

The term “pharmaceutically acceptable” as used herein means beingapproved by a regulatory agency of the Federal or a state government, orlisted in the U.S. Pharmacopeia, European Pharmacopeia or othergenerally recognized Pharmacopeia for use in animals, and moreparticularly in humans.

“Polyclonal antibodies” as used herein refers to an antibody populationgenerated in an immunogenic response to a protein having many epitopesand thus includes a variety of different antibodies directed to the sameand to different epitopes within the protein. Methods for producingpolyclonal antibodies are known in the art (See, e.g., see, for example,Chapter 11 in: Short Protocols in Molecular Biology, (2002) 5th Ed.,Ausubel et al., eds., John Wiley and Sons, New York).

As used herein, the term “polynucleotide,” “nucleotide,” nucleic acid”“nucleic acid molecule” and other similar terms are used interchangeableand include DNA, RNA, mRNA and the like.

A “pre-cancerous cell” refers to a cell that has an abnormal appearancesuch as a difference in size or shape in comparison to cells of thesurrounding tissue or normal cells of its cell type, but are notinvasive. The appearance of pre-cancerous cells can be suggestive of anincreased cancer risk. Pre-cancerous cells expressing C10orf54 can beidentified using methods disclosed herein, which can include analyzing asample of cells from a patient.

As used herein, the terms “prevent,” “preventing,” and “prevention”refer to the total or partial inhibition of the development, recurrence,onset or spread of a C10orf54-mediated disease and/or symptom relatedthereto, resulting from the administration of a therapy or combinationof therapies provided herein (e.g., a combination of prophylactic ortherapeutic agents, such as an antibody provided herein).

As used herein, the term “prophylactic agent” refers to any agent thatcan totally or partially inhibit the development, recurrence, onset orspread of a C10orf54-mediated disease and/or symptom related thereto ina subject. In certain embodiments, the term “prophylactic agent” refersto an anti-C10orf54 antibody provided herein. In certain otherembodiments, the term “prophylactic agent” refers to an agent other thanan anti-C10orf54 antibody provided herein. In certain embodiments, aprophylactic agent is an agent which is known to be useful to or hasbeen or is currently being used to prevent a C10orf54-mediated diseaseand/or a symptom related thereto or impede the onset, development,progression and/or severity of a C10orf54-mediated disease and/or asymptom related thereto. In specific embodiments, the prophylactic agentis a humanized anti-C10orf54 antibody, such as a humanized anti-C10orf54monoclonal antibody.

In certain embodiments, a “prophylactically effective serum titer” isthe serum titer in a subject, preferably a human, that totally orpartially inhibits the development, recurrence, onset or spread of aC10orf54-mediated disease and/or symptom related thereto in the subject.

The term “recombinant antibody” refers to an antibody that is prepared,expressed, created or isolated by recombinant means. Recombinantantibodies can be antibodies expressed using a recombinant expressionvector transfected into a host cell, antibodies isolated from arecombinant, combinatorial antibody library, antibodies isolated from ananimal (e.g., a mouse or cow) that is transgenic and/or transchromosomalfor human immunoglobulin genes (see e.g., Taylor, L. D. et al. (1992)Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed,created or isolated by any other means that involves splicing ofimmunoglobulin gene sequences to other DNA sequences. Such recombinantantibodies can have variable and constant regions derived from humangermline immunoglobulin sequences (See Kabat, E. A. et al. (1991)Sequences of Proteins of Immunological Interest, Fifth Edition, U.S.Department of Health and Human Services, NIH Publication No. 91-3242).In certain embodiments, however, such recombinant antibodies aresubjected to in vitro mutagenesis (or, when an animal transgenic forhuman Ig sequences is used, in vivo somatic mutagenesis) and thus theamino acid sequences of the VH and VL regions of the recombinantantibodies are sequences that, while derived from and related to humangermline VH and VL sequences, may not naturally exist within the humanantibody germline repertoire in vivo.

The term “serum titer” as used herein refers to an average serum titerin a population of least 10, such as at least 20, or at least 40subjects, up to about 100, 1000 or more.

As used herein, the term “side effects” encompasses unwanted and adverseeffects of a therapy (e.g., a prophylactic or therapeutic agent).Unwanted effects are not necessarily adverse. An adverse effect from atherapy (e.g., a prophylactic or therapeutic agent) might be harmful oruncomfortable or risky. Examples of side effects include, diarrhea,cough, gastroenteritis, wheezing, nausea, vomiting, anorexia, abdominalcramping, fever, pain, loss of body weight, dehydration, alopecia,dyspenea, insomnia, dizziness, mucositis, nerve and muscle effects,fatigue, dry mouth, and loss of appetite, rashes or swellings at thesite of administration, flu-like symptoms such as fever, chills andfatigue, digestive tract problems and allergic reactions. Additionalundesired effects experienced by patients are numerous and known in theart. Many are described in the Physician's Desk Reference (67^(th) ed.,2013).

As used herein, the terms “subject” and “patient” are usedinterchangeably. As used herein, in certain embodiments, a subject is amammal, such as a non-primate (e.g., cows, pigs, horses, cats, dogs,rats, etc.) or a primate (e.g., monkey and human). In specificembodiments, the subject is a human. In one embodiment, the subject is amammal (e.g., a human) having a C10orf54-mediated disease. In anotherembodiment, the subject is a mammal (e.g., a human) at risk ofdeveloping a C10orf54-mediated disease.

As used herein “substantially all” refers to refers to at least about60%, at least about 70%, at least about 75%, at least about 80%, atleast about 85%, at least about 90%, at least about 95%, at least about98%, at least about 99%, or about 100%.

As used herein, the term “therapeutic agent” refers to any agent thatcan be used in treating, preventing or alleviating a disease, disorderor condition, including in the treatment, prevention or alleviation ofone or more symptoms of a C10orf54-mediated disease, disorder, orcondition and/or a symptom related thereto. In certain embodiments, atherapeutic agent refers to an antibody provided herein. In certainother embodiments, a therapeutic agent refers to an agent other than anantibody provided herein. In certain embodiments, a therapeutic agent isan agent which is known to be useful for, or has been or is currentlybeing used for the treatment, prevention or alleviation of one or moresymptoms of a C10orf54-mediated disease, disorder, condition, or asymptom related thereto.

The combination of therapies (e.g., use of therapeutic agents) can bemore effective than the additive effects of any two or more singletherapy. For example, a synergistic effect of a combination oftherapeutic agents permits the use of lower dosages of one or more ofthe agents and/or less frequent administration of the agents to asubject with a C10orf54-mediated disease. The ability to utilize lowerdosages of therapeutic therapies and/or to administer the therapies lessfrequently reduces the toxicity associated with the administration ofthe therapies to a subject without reducing the efficacy of thetherapies in the prevention, treatment or alleviation of one or moresymptom of a C10orf54-mediated disease. In addition, a synergisticeffect can result in improved efficacy of therapies in the prevention,treatment or alleviation of one or more symptom of a C10orf54-mediateddisease. Finally, synergistic effect of a combination of therapies(e.g., therapeutic agents) may avoid or reduce adverse or unwanted sideeffects associated with the use of any single therapy.

The term “therapeutically effective amount” as used herein refers to theamount of a therapeutic agent (e.g., an antibody provided herein or anyother therapeutic agent provided herein) that is sufficient to reduceand/or ameliorate the severity and/or duration of a given disease and/ora symptom related thereto. A therapeutically effective amount of atherapeutic agent can be an amount necessary for the reduction oramelioration of the advancement or progression of a given disease,reduction or amelioration of the recurrence, development or onset of agiven disease, and/or to improve or enhance the prophylactic ortherapeutic effect of another therapy (e.g., a therapy other than theadministration of an antibody provided herein).

In certain embodiments, a “therapeutically effective serum titer” is theserum titer in a subject, preferably a human, that reduces the severity,the duration and/or the symptoms associated with a C10orf54-mediateddisease in the subject.

As used herein, the term “therapy” refers to any protocol, method and/oragent that can be used in the prevention, management, treatment and/oramelioration of a C10orf54-mediated disease. In certain embodiments, theterms “therapies” and “therapy” refer to a biological therapy,supportive therapy, and/or other therapies useful in the prevention,management, treatment and/or amelioration of a C10orf54-mediated diseaseknown to one of skill in the art such as medical personnel.

The term “thiol,” as used herein, refers to the radical —SH.

As used herein, the terms “treat,” “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity, and/orduration of a C10orf54-mediated disease resulting from theadministration of one or more therapies (including, but not limited to,the administration of one or more therapeutic agents, such as anantibody provided herein). In specific embodiments, such terms refer tothe reduction or inhibition of cancer or tumor formation. In otherspecific embodiments, such term refers to the reduction or ameliorationof the progression, severity and/or duration of graft-versus-hostdisease. In yet other specific embodiments, such terms refer to thereduction or amelioration of the progression, severity, and/or durationof a disease that is responsive to immune modulation, such modulationresulting from increasing T cell activation, increasing T cellproliferation or increasing cytokine production.

“Tubulysin” includes both the natural products described as tubulysins,such as by Sasse et al. and other authors mentioned in the Descriptionof the related art, and also the tubulysin analogs described in USPatent Application Publication No. US 2011/0021568 A1. Tubulysinsdisclosed in the present application are noted herein and may includethe tubulysins of the formulae T3 and T4, and other tubulysins where theterminal N-methylpiperidine has been replaced by an unsubstitutedpiperidine, allowing amide bond formation with a linker.

The term “variable domain” or “variable region” refers to a portion ofthe light or heavy chains of an antibody that is generally located atthe amino-terminal of the light or heavy chain and has a length of about120 to 130 amino acids in the heavy chain and about 100 to 110 aminoacids in the light chain, and are used in the binding and specificity ofeach particular antibody for its particular antigen. The variabledomains differ extensively in sequence between different antibodies. Thevariability in sequence is concentrated in the CDRs while the lessvariable portions in the variable domain are referred to as frameworkregions (FR). The CDRs of the light and heavy chains are primarilyresponsible for the interaction of the antibody with antigen. Inspecific embodiments, the variable region is a human variable region.

The term “variable domain residue numbering as in Kabat” or “amino acidposition numbering as in Kabat”, and variations thereof, refers to thenumbering system used for heavy chain variable domains or light chainvariable domains of the compilation of antibodies in Kabat et al.,Sequences of Proteins of Immunological Interest, 5th Ed. Public HealthService, National Institutes of Health, Bethesda, Md. (1991). Using thisnumbering system, the actual linear amino acid sequence may containfewer or additional amino acids corresponding to a shortening of, orinsertion into, a FR or CDR of the variable domain. For example, a heavychain variable domain may include a single amino acid insert (residue52a according to Kabat) after residue 52 of H2 and inserted residues(e.g. residues 82a, 82b, and 82c, etc, according to Kabat) after heavychain FR residue 82. The Kabat numbering of residues may be determinedfor a given antibody by alignment at regions of homology of the sequenceof the antibody with a “standard” Kabat numbered sequence. The Kabatnumbering system is generally used when referring to a residue in thevariable domain (approximately residues 1-107 of the light chain andresidues 1-113 of the heavy chain) (e.g, Kabat et al., Sequences ofImmunological Interest. 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md. (1991)). The “EU numbering system”or “EU index” is generally used when referring to a residue in animmunoglobulin heavy chain constant region (e.g., the EU index reportedin Kabat et al., supra). The “EU index as in Kabat” refers to theresidue numbering of the human IgG 1 EU antibody. Unless statedotherwise herein, references to residue numbers in the variable domainof antibodies means residue numbering by the Kabat numbering system.Other numbering systems have been described, including, for example, byAbM, Chothia, Contact and IMGT. Various numbering systems areillustrated in FIGS. 16A and 16B.

The term “variant” when used in relation to C10orf54 or to ananti-C10orf54 antibody refers to a peptide or polypeptide comprising oneor more (such as, for example, about 1 to about 25, about 1 to about 20,about 1 to about 15, about 1 to about 10, or about 1 to about 5) aminoacid sequence substitutions, deletions, and/or additions as compared toa native or unmodified sequence. For example, a C10orf54 variant mayresult from one or more (such as, for example, about 1 to about 25,about 1 to about 20, about 1 to about 15, about 1 to about 10, or about1 to about 5) changes to an amino acid sequence of native C10orf54. Alsoby way of example, a variant of an anti-C10orf54 antibody may resultfrom one or more (such as, for example, about 1 to about 25, about 1 toabout 20, about 1 to about 15, about 1 to about 10, or about 1 to about5) changes to an amino acid sequence of a native or previouslyunmodified anti-C10orf54 antibody. Variants may be naturally occurring,such as allelic or splice variants, or may be artificially constructed.Polypeptide variants may be prepared from the corresponding nucleic acidmolecules encoding the variants. In specific embodiments, the C10orf54variant or anti-C10orf54 antibody variant at least retains C10orf54 oranti-C10orf54 antibody functional activity, respectively. In specificembodiments, an anti-C10orf54 antibody variant binds C10orf54 and/or isantagonistic to C10orf54 activity. In specific embodiments, ananti-C10orf54 antibody variant binds C10orf54 and/or is agonistic toC10orf54 activity. In certain embodiments, the variant is encoded by asingle nucleotide polymorphism (SNP) variant of a nucleic acid moleculethat encodes C10orf54 or anti-C10orf54 antibody VH or VL regions orsubregions.

The term “vector” refers to a substance that is used to introduce anucleic acid molecule into a host cell. Vectors applicable for useinclude, for example, expression vectors, plasmids, phage vectors, viralvectors, episomes and artificial chromosomes, which can includeselection sequences or markers operable for stable integration into ahost cell's chromosome. Additionally, the vectors can include one ormore selectable marker genes and appropriate expression controlsequences. Selectable marker genes that can be included, for example,provide resistance to antibiotics or toxins, complement auxotrophicdeficiencies, or supply critical nutrients not in the culture media.Expression control sequences can include constitutive and induciblepromoters, transcription enhancers, transcription terminators, and thelike which are well known in the art. When two or more nucleic acidmolecules are to be co-expressed (e.g. both an antibody heavy and lightchain), both nucleic acid molecules can be inserted, for example, into asingle expression vector or in separate expression vectors. For singlevector expression, the encoding nucleic acids can be operationallylinked to one common expression control sequence or linked to differentexpression control sequences, such as one inducible promoter and oneconstitutive promoter. The introduction of nucleic acid molecules into ahost cell can be confirmed using methods well known in the art. Suchmethods include, for example, nucleic acid analysis such as Northernblots or polymerase chain reaction (PCR) amplification of mRNA, orimmunoblotting for expression of gene products, or other suitableanalytical methods to test the expression of an introduced nucleic acidsequence or its corresponding gene product. It is understood by thoseskilled in the art that the nucleic acid molecule is expressed in asufficient amount to produce the desired product (e.g. an anti-C10orf54antibody provided herein), and it is further understood that expressionlevels can be optimized to obtain sufficient expression using methodswell known in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B shows the protein expression level of C10orf54 that wasidentified and quantified by sTAg analysis in AML and BMMC samples andrelevant control.

FIG. 2 shows FACS analysis of 23 primary AML-BM-MNC and 3 normal BM-MNCsamples using anti-C10orf54 antibody 76E1.

FIGS. 3A and 3B show humanized sequences for murine monoclonal antibody76E1 VH region. SEQ ID NOS: 1, 7, 8, 12-15 and 82 are depicted.

FIGS. 4A and 4B show humanized sequences for murine monoclonal antibody141A VH region. SEQ ID NOS: 2, 7, 8, 16-19 and 82 are depicted.

FIGS. 5A and 5B show humanized sequences for murine monoclonal antibody175A VH region. SEQ ID NOS: 3, 7, 8, 20-23 and 82 are depicted.

FIGS. 6A and 6B show humanized sequences for murine monoclonal antibody76E1 VL region. SEQ ID NOS: 4, 9, 10, 24, 25 and 94 are depicted.

FIGS. 7A and 7B show humanized sequences for murine monoclonal antibody141A VL region. SEQ ID NOS: 5, 10, 11, 26, 27 and 94 are depicted.

FIGS. 8A and 8B show humanized sequences for murine monoclonal antibody175A VL region. SEQ ID NOS: 6, 9, 10, 28, 29 and 94 are depicted.

FIG. 9 shows pseudo-sequences of VH and VL domains of murine monoclonalantibodies 76E1, 141A and 175A (SEQ ID NOS: 1143-1148). CDRs areidentified in bold.

FIG. 10 shows anti-C10orf54 antibody treatment induces strong tumorgrowth inhibition in established Kasumi-3 tumors.

FIG. 11 shows murine 175A anti-C10orf54 antibody treatment inducesstrong tumor growth inhibition in established Kasumi-3 tumors.

FIG. 12 shows results of a secondary ADC assay using anti-C10orf54antibodies in a cell viability assay with C10orf54 expressing sarcomaline.

FIGS. 13 and 14 show activity of unconjugated and MMAF conjugatedanti-C10orf54 antibodies in a cell viability assay using C10orf54expressing sarcoma lines and parental sarcoma line.

FIG. 15 shows results of treatment with unconjugated and MMAF conjugatedanti-C10orf54 antibodies in a tumor model using a C10orf54 expressingsarcoma line and parental sarcoma line.

FIGS. 16A and 16B shows a sequence alignment of the variable heavychains and variable light chains of the anti-C10orf54 murine antibodiesdesignated 76E1, 141A and 175A (SEQ ID NOS:1-6). Boundaries of CDR's areindicated by Kabat, AbM, Chothia, Contact and IMGT numbering.

FIGS. 17A and 17B shows a sequence alignment of the variable heavychains and variable light chains of exemplary humanized anti-C10orf54antibodies designated hu76E1, hu141A and hu175A (SEQ ID NOS: 1135-1137for heavy chains; SEQ ID NOS: 1139-1141 for light chains) and thecorresponding consensus sequences between hu76E1 and hu175A (SEQ ID NO:1138 for the heavy chain; SEQ ID NO: 1142 for the light chain). Residuesindicated just below that alignment indicate specific residues that canbe varied at the above “X” position in the consensus sequence.

DETAILED DESCRIPTION

Provided herein are antibodies that bind to C10orf54, including aC10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54epitope. Such antibodies include humanized anti-C10orf54 antibodies.Also provided are antibodies (e.g., humanized anti-C10orf54 antibodies)that competitively block and anti-C10orf54 antibody provided herein frombinding to a C10orf54 polypeptide. The anti-C10orf54 antibodies (e.g.,humanized anti-C10orf54 antibodies) provided herein can also beconjugated or recombinantly fused to a diagnostic agent, detectableagent or therapeutic agent (e.g., antibody-drug conjugate). Furtherprovided are compositions comprising an anti-C10orf54 antibody (e.g., ahumanized anti-C10orf54 antibody). For example, a detectable agent maybe a detectable probe.

Also provided herein are isolated nucleic acid molecules encoding a VHchain, VL chain, VH domain, VL domain, VH CDR1, VH CDR2, VH CDR3, VLCDR1, VL CDR2, and/or VL CDR3 of anti-C10orf54 antibodies that bind to aC10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54epitope. Further provided are vectors and host cells comprising nucleicacid molecules encoding anti-C10orf54 antibodies that bind to a C10orf54polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.Also provided are methods of making antibodies that bind to a C10orf54polypeptide, a C10orf54 polypeptide fragment, or a C10orf54 epitope.

Methods of using the anti-C10orf54 antibodies (e.g., humanizedanti-C10orf54 antibodies) are provided. Methods include treating,preventing or alleviating a disease, disorder or condition, includingone or more symptoms of a disease, disorder or condition, comprisingadministering a therapeutically effective amount of an anti-C10orf54antibody, including an antibody-drug conjugate (ADC) comprising ananti-C10orf54 antibody, provided herein to a subject, thereby treating,preventing or alleviating the disease, disorder or condition, includingone or more symptoms of the disease, disorder or condition. In someembodiments the anti-C10orf54 antibodies are humanized antibodies thatbind to a C10orf54 polypeptide, a C10orf54 polypeptide fragment or aC10orf54 epitope. In one embodiment, the disease, disorder or conditionis caused by or otherwise associated with C10orf54, including by orassociated with C10orf54-expressing cells (e.g., tumor cells,myeloid-derived suppressor cells (MDSC), suppressive dendritic cells(suppressive DC), and/or regulatory T cells (T regs)). In certainembodiments, the disease is a cancer, such as a leukemia, a bladdercancer or a fibrosarcoma. In one embodiment, the leukemia is an acutemyeloid leukemia (AML). In other embodiments, the disease isgraft-versus-host disease (GVHD). Additional methods provided includeusing an anti-C10orf54 antibody with C10orf54 binding activity forC10orf54-expressing cells, provided herein, for example, as anunconjugated antibody or conjugated antibody (ADC), including to inhibitand/or kill the C10orf54-expressing cells (e.g., with anti-tumoractivity to mediate an anti-tumor effect). In certain embodiments, theanti-C10orf54 antibodies, including ADCs comprising the anti-C10orf54antibodies, provided herein inhibit C10orf54-mediated suppressoractivity on T cells (e.g., to allow an effective anti-tumor immuneresponse). In certain embodiments, the anti-C10orf54 antibodies providedherein directly kill C10orf54-expressing cells (e.g., C10orf54-bearingtumor cells, myeloid-derived suppressor cells (MDSC), suppressivedendritic cells (suppressive DC), and/or regulatory T cells (T regs)),for example, via antibody-dependent cellular cytotoxicity (ADCC) and/orcomplement-dependent cytotoxicity (CDC) In certain embodiments, antibodydrug conjugates (ADCs) comprising anti-C10orf54 antibodies providedherein directly kill C10orf54-expressing cells including by binding tocells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressorcells (MDSC), suppressive dendritic cells (suppressive DC), and/orregulatory T cells (T regs)), for example, by allowing internalizationof the cytotoxic drug. In any of the above embodiments, theanti-C10orf54 antibody can be a humanized anti-C10orf54 antibodyprovided herein that binds to a C10orf54 polypeptide, a C10orf54polypeptide fragment or a C10orf54 epitope. In any of the aboveembodiments, the anti-C10orf54 antibody can be a humanized anti-C10orf54antibody provided herein that binds to a C10orf54 polypeptide, aC10orf54 polypeptide fragment or a C10orf54 epitope.

Additional methods of using an anti-C10orf54 antibody are provided.

The methods include methods of inhibiting the growth of cells and/orkilling cells having cell surface expression of C10orf54 comprisingcontacting the cells with an effective amount of an anti-C10orf54antibody or antibody-drug conjugates provided herein. In one embodiment,the cell is a regulatory T cell (e.g., a CD4⁺ Foxp3⁺ regulatory T cell).In other embodiments, the cell is a myeloid-derived suppressor cell(e.g., a CD11b⁺ or CD11b^(high) myeloid-derived suppressor cell) or asuppressive dendritic cell (e.g., a CD11b⁺ or CD11b^(high) dendriticcell). In other embodiments, the cell is a cancerous or pre-cancerouscell. Additional methods provided include using an anti-C10orf54antibody with C10orf54 binding activity for C10orf54-expressing cellsprovided herein, for example, as an unconjugated antibody or conjugatedantibody (ADC) including to inhibit and/or kill C10orf54-expressingcells (e.g., with anti-tumor activity to mediate an anti-tumor effect).In certain embodiments, the anti-C10orf54 antibodies, including ADCscomprising the anti-C10orf54 antibodies, provided herein inhibitC10orf54-mediated suppressor activity on T cells (e.g., to allow aneffective anti-tumor immune response). In certain embodiments, theanti-C10orf54 antibodies provided herein directly killC10orf54-expressing cells (e.g., C10orf54-bearing tumor cells,myeloid-derived suppressor cells (MDSC), suppressive dendritic cells(suppressive DC), and/or regulatory T cells (T regs)), for example, viaantibody-dependent cellular cytotoxicity (ADCC) and/orcomplement-dependent cytotoxicity (CDC) In certain embodiments, antibodydrug conjugates (ADCs) comprising anti-C10orf54 antibodies providedherein directly kill C10orf54-expressing cells including by binding tocells expressing C10orf54 (e.g., tumor cells, myeloid-derived suppressorcells (MDSC), suppressive dendritic cells (suppressive DC), and/orregulatory T cells (T regs)), for example, by allowing internalizationof the cytotoxic drug. In any of the above embodiments, theanti-C10orf54 antibody can be a humanized anti-C10orf54 antibodyprovided herein that binds to a C10orf54 polypeptide, a C10orf54polypeptide fragment or a C10orf54 epitope.

The methods include methods of modulating an immune response in asubject comprising administering an effective amount of an anti-C10orf54antibody (e.g., a humanized anti-C10orf54 antibody) provided herein to asubject. In one embodiment, the modulating comprises increasing T cellactivation. In other embodiment, the modulating comprises increasing Tcell proliferation. In another embodiment, the modulating comprisesincreasing cytokine production.

The methods include methods for detecting C10orf54 in a samplecomprising contacting the sample with an anti-C10orf54 antibody (e.g., ahumanized anti-C10orf54 antibody) provided herein, such as an antibodythat comprises a detectable agent. In certain embodiments, the samplecomprises a cell expressing C10orf54 on its surface.

The methods include methods of treating cancers comprising administeringto a subject an anti-C10orf54 antibody or an antibody-drug conjugate(ADC) comprising an anti-C10orf54 (e.g., an ADC of the formula A-L-CTX,wherein A is the antibody, L is a linker, and CTX is a cytotoxic agent)in a therapeutically effective amount, including in an amount effectiveto kill a C10orf54-expressing cell (e.g., tumor cell, myeloid-derivedsuppressor cell (MDSC), suppressive dendritic cell (suppressive DC),and/or regulatory T cell (T reg)). In some embodiments the cancer isacute myeloid leukemia (AML). In any of the above embodiments, theanti-C10orf54 antibody can be a humanized anti-C10orf54 antibodyprovided herein that binds to a C10orf54 polypeptide, a C10orf54polypeptide fragment or a C10orf54 epitope.

The methods include methods of killing C10orf54-expressing cells (e.g.,tumor cells, myeloid-derived suppressor cells (MDSC), suppressivedendritic cells (suppressive DC), and/or regulatory T cells (T reg))comprising contacting a C10orf54-expressing cell (e.g., tumor cell,myeloid-derived suppressor cell (MDSC), suppressive dendritic cell(suppressive DC), and/or regulatory T cell (T regs)) with an amount ofan anti-C10orf54 antibody or an antibody-drug conjugate (ADC) comprisingan anti-C10orf54 antibody (e.g., an ADC of the formula A-L-CTX, whereinA is the antibody, L is a linker, and CTX is a cytotoxic agent)effective to kill the cell (e.g., tumor cell, myeloid-derived suppressorcell (MDSC), suppressive dendritic cell (suppressive DC), and/orregulatory T cell (T reg)). In some embodiments, the tumor cell is anAML cell. In any of the above embodiments, the anti-C10orf54 antibodycan be a humanized anti-C10orf54 antibody provided herein that binds toa C10orf54 polypeptide, a C10orf54 polypeptide fragment or a C10orf54epitope.

In one embodiment, provided herein is a kit comprising an anti-C10orf54antibody (e.g., a humanized anti-C10orf54 antibody) that binds to aC10orf54 polypeptide, a C10orf54 polypeptide fragment, or a C10orf54epitope provided herein. In some embodiments, the kits comprise anantibody-drug conjugate (ADC) wherein the antibody is an anti-C10orf54antibody (e.g., a humanized anti-C10orf54 antibody).

Antibodies

In some embodiments, provided herein are antibodies that bind toC10orf54, including a C10orf54 polypeptide, a C10orf54 polypeptidefragment or a C10orf54 epitope. In some embodiments the anti-C10orf54antibodies are humanized antibodies that bind C10orf54, including to aC10orf54 polypeptide, a C10orf54 polypeptide fragment or a C10orf54epitope.

In certain embodiments, the anti-C10orf54 antibody comprises a VHdomain, VL domain, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and/orVL CDR3 of the murine monoclonal antibody 175A, 76E1 or 141A as depictedin Table 2 and FIGS. 3-8. Accordingly, in some aspects, the VH domaincomprises the amino acid sequence of SEQ ID NO:1. In some embodiments,the VH domain comprises the amino acid sequence of SEQ ID NO:2. In someembodiments, the VH domain comprises the amino acid sequence of SEQ IDNO:3. In some embodiments, the VL domain comprises the amino acidsequence of SEQ ID NO:4. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO:5. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO:6.

TABLE 2 Murine Antibody Sequences Murine Antibody VH Domain* VL Domain*76E1 EVQLLQSGPELEKPGASVKISCKAS DVLMTQTPLSLPVSLGDQASISCRSSQGYSFTGYNMNWVKQSNGKSLEWIG SIVHSNGNTYLEWYLQKPGQSPKLLIYNIDPYYDYTSYNLKFKDKATLTVDK KVSNRFSGVPDRFSGSGSGTDFTLKINSSSTAYMQLKSLTSEDSAVYYCATS RVEAEDLGVYYCFQGSHVPWTFGGGTTMITPFDYWGQGTTLTVSS (SEQ ID KLEIK (SEQ ID NO: 4) NO: 1) 141AQVQLQQSGAELMKPGASVKISCKAT QIVLSQSPAILSASPGEKVTMTCRASSSGYTFSRYWIEWVKQRPGHGLEWIG LSYMHWYQQKPGSSPKPWIYATSNLAEILPGSGSTNYNEKFKGKATFTADT SGVPARFSGSGSGTSYSLTISRVEAEDSSNTAYMQLSSLTSEDSAVYYCAGE AATYYCQQWSSNPYTFGGGTKLEIKEVYDGYPWFGYWGQGTLVTVSA (SEQ ID NO: 5) (SEQ ID NO: 2) 175AQVQLQQSGAELMKPGASVKISCKAT DVLMTQTPLSLPVSLGDQASISCRSSQGYTFSTHWIEWVKQRPGHGLEWIG SIVHSNGNTYLEWYLQKPGQSPKLLIYEILPGSGSTSYNEKFKGKATFTADT KLSNRFSGVPDRFSGSGSGTDFTLKISSSNTAYMQLSSLTSEDSAVYYCAR RVEAEDLGVYYCFQGSHFPYTFGGGTWLLYYYAMDYWGQGTSVTVSS KLEIK (SEQ ID NO: 6) (SEQ ID NO: 3) *Bold aminoacid residues represent CDR sequences (CDR1-first bolded sequence;CDR2-second bolded sequence; CDR3-third bolded sequence)

In certain embodiments, the anti-C10orf54 antibody comprises a VH FR1,VH FR2, VH FR3, VH FR4, VL FR1, VL FR2, VL FR3, and/or VL FR4 of a humangermline immunoglobulin amino acid sequence or a variant thereof. Forexample, in some embodiments, the anti-C10orf54 antibody comprises a VHFR1, VH FR2, VH FR3, and/or VH FR4 depicted in a human germline sequenceidentified in Table 3. Accordingly, in some embodiments, theanti-C10orf54 antibody comprises a VH FR1, VH FR2, VH FR3, and/or VH FR4of the human germline IGHV1-18 (SEQ ID NO:7) and IGHJ4-01 (SEQ ID NO:82). In some embodiments, the anti-C10orf54 antibody comprises a VH FR1,VH FR2, VH FR3, and/or VH FR4 of the human germline IGHV3-48 (SEQ IDNO:8) and IGHJ4-01 (SEQ ID NO: 82). In some embodiments, theanti-C10orf54 antibody comprises a VL FR1, VL FR2, VL FR3, and/or VL FR4of the human germline IGKV2-28 (SEQ ID NO:9) and IGKJ2-1 (SEQ ID NO:94).In some embodiments, the anti-C10orf54 antibody comprises a VL FR1, VLFR2, VL FR3, and/or VL FR4 of the human germline IGKV1-39 (SEQ ID NO:10)and IGKJ2-1 (SEQ ID NO:94). In some embodiments, the anti-C10orf54antibody comprises a VL FR1, VL FR2, VL FR3, and/or VL FR4 of the humangermline IGKV3-20 (SEQ ID NO:10) and IGKJ2-1 (SEQ ID NO:94).

TABLE 3 Human Germline Immunoglobulin Amino Acid SequencesHuman Germline Amino Acid Sequence SEQ ID NO: Heavy Chain IMGT IGHV1-18QVQLVQSGAEVKKPGASVKVSCKASGYTFT (SEQ ID NO: 7)SYGISWVRQAPGQGLEWMGWISAYNGNTN YAQKLQGRVTMTTDTSTSTAYMELRSLRSD DTAVYYCARIMGT IGHV3-48 EVQLVESGGGLVQPGGSLRLSCAASGFTFSS (SEQ ID NO: 8)YSMNWVRQAPGKGLEWVSYISSSSSTIYYAD SVKGRFTISRDNAKNSLYLQMNSLRAEDTAV YYCARJoining region YFDYWGQGTLVTVSS (SEQ ID NO: 82) IMGT IGHJ4-01 Light ChainIMGT IGKV2-28 DIVMTQSPLSLPVTPGEPASISCRSSQSLLHS (SEQ ID NO: 9)NGYNYLDWYLQKPGQSPQLLIYLGSNRASG VPDRFSGSGSGTDFTLKISRVEAEDVGVYYC MQALQTPIMGT IGKV1-39 DIQMTQSPSSLSASVGDRVTITCRASQSISSY (SEQ ID NO: 10)LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS GSGSGTDFTLTISSLQPEDFATYYCQQSYST PIMGT IGKV3-20 EIVLTQSPGTLSLSPGERATLSCRASQSVSSS (SEQ ID NO: 11)YLAWYQQKPGQAPRLLIYGASSRATGIPDRF SGSGSGTDFTLTISRLEPEDFAVYYCQQYGS SPJoining region YTFGQGTKLEIK (SEQ ID NO: 94) IMGT IGKJ2-01 *Bold aminoacid residues represent CDR sequences (CDR1-first bolded sequence;CDR2-second bolded sequence; CDR3-third bolded sequence)

In certain embodiments, antibodies that bind to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprise aVH domain having an amino acid sequence identified in Table 4 or FIGS.3-8 and/or a VL domain having an amino acid sequence identified in Table4 or FIGS. 3-8.

TABLE 4 Humanized Antibody Amino Acid Sequences of VH and VL DomainsMurine Humanized VH Domains Humanized VL Domains Clone (SEQ ID NO:)(SEQ ID NO:) 76E1 QVQLVQSGAEVKKPGASVKVSCKA DIVMTQSPLSLPVTPGEPASISCRSSQSSGYSFTGYNMNWVRQAPGQGLEW IVHSNGNTYLEWYLQKPGQSPQLLIYKMGNIDPYYDYTSYNLKFKDRVTMTT VSNRFSGVPDRFSGSGSGTDFTLKISRDTSTSTAYMELRSLRSDDTAVYYCA VEAEDVGVYYCFQGSHVPWTFGQGTKRSTMITPFDYWGQGTLVTVSS (SEQ LEK (SEQ ID NO: 24) ID NO: 12)QVQLVQSGAEVKKPGASVKVSCKA DIQMTQSPSSLSASVGDRVTITCRSSQSGYSFTGYNMNWVRQAPGQGLEW SIVHSNGNTYLEWYQQKPGKAPKLLIYMGNIDPYYDYTSYAQKLQGRVTMT KVSNRFSGVPSRFSGSGSGTDFTLTISTDTSTSTAYMELRSLRSDDTAVYYC SLQPEDFATYYCFQGSHVPWTFGQGTARSTMITPFDYWGQGTLVTVSS KLEIK (SEQ ID NO: 25) (SEQ ID NO: 13)EVQLVESGGGLVQPGGSLRLSCAA SGYSFTGYNMNWVRQAPGKGLEWVSNIDPYYDYTSYNLKEKDRFTISRD NAKNSLYLQMNSLRAEDTAVYYCARSTMITPFDYWGQGTLVTVSS (SEQ ID NO: 14) EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYNMNWVRQAPGKGLEW VSNIDPYYDYTSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCA RSTMITPFDYWGQGTLVTVSS (SEQ ID NO: 15) 141AQVQLVQSGAEVKKPGASVKVSCKA EIVLTQSPGTLSLSPGERATLSCRASSSSGYTFSRYWIEWVRQAPGQGLEW LSYMHWYQQKPGQAPRLLIYATSNLASMGEILPGSGSTNYNEKFKGRVTMTT GIPDRFSGSGSGTDFTLTISRLEPEDFADTSTSTAYMELRSLRSDDTAVYYCA VYYCQQWSSNPYTFGQGTKLEIKREEVYDGYPWFGYWGQGTLVTVS (SEQ ID NO: 26) S (SEQ ID NO: 16)QVQLVQSGAEVKKPGASVKVSCKA DIQMTQSPSSLSASVGDRVTITCRASSSGYTFSRYWIEWVRQAPGQGLEW SLSYMHWYQQKPGKAPKLLIYATSNLAMGEILPGSGSTNYAQKLQGRVTMT SGVPSRFSGSGSGTDFTLTISSLQPEDTDISTSTAYMELRSLRSDDTAVYYC FATYYCQQWSSNPYTFGQGTKLEIKAREEVYDGYPWFGYWGQGTLVTV (SEQ ID NO: 27) SS (SEQ ID NO: 17)EVQLVESGGGLVQPGGSLRLSCAA SGYTFSRYWIEWVRQAPGKGLEWVSEILPGSGSTNYNEKFKGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCAREEVYDGYPWFGYWGQGTLVTVSS (SEQ ID NO: 18) EVQLVESGGGLVQPGGSLRLSCAASGYTFSRYWIEWVRQAPGKGLEWV SEILPGSGSTNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCA REEVYDGYPWFGYWGQGTLVTVS S (SEQ ID NO: 19) 175AQVQLVQSGAEVKKPGASVKVSCKA DIVMTQSPLSLPVTPGEPASISCRSSQSSGYTFSTHWIEWVRQAPGQGLEW IVHSNGNTYLEWYLQKPGQSPQLLIYKMGEILPGSGSTSYNEKFKGRVTMTT LSNRFSGVPDRFSGSGSGTDFTLKISRDTSTSTAYMELRSLRSDDTAVYYCA VEAEDVGVYYCFQGSHFPYTFGQGTKRWLLYYYAMDYWGQGTLVTVSS LEIK (SEQ ID NO: 28) (SEQ ID NO: 20)QVQLVQSGAEVKKPGASVKVSCKA DIQMTQSPSSLSASVGDRVTITCRSSQSGYTFSTHWIEWVRQAPGQGLEW SIVHSNGNTYLEWYQQKPGKAPKLLIYMGEILPGSGSTSYAQKLQGRVTMTT KLSNRFSGVPSRFSGSGSGTDFTLTISDTSTSTAYMELRSLRSDDTAVYYCA SLQPEDFATYYCFQGSHFPYTFGQGTRWLLYYYAMDYWGQGTLVTVSS KLEIK (SEQ ID NO: 29) (SEQ ID NO: 21)EVQLVESGGGLVQPGGSLRLSCAA SGYTFSTHWIEWVRQAPGKGLEWVSEILPGSGSTSYNEKFKGRFTISRDN AKNSLYLQMNSLRAEDTAVYYCARWLLYYYAMDYWGQGTLVTVSS (SEQ ID NO: 22) EVQLVESGGGLVQPGGSLRLSCAASGYTFSTHWIEWVRQAPGKGLEWV SEILPGSGSTSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR WLLYYYAMDYWGQGTLVTVSS (SEQ ID NO: 23)

Accordingly, in some embodiments, antibodies that bind to C10orf54(e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54epitope) comprise a VH domain having the amino acid sequence of SEQ IDNOS:20, 21, 22 or 23 and/or a VL domain having the amino acid sequenceof SEQ ID NO:28 or 29. In one embodiment, an antibody that binds toC10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope) comprises a VH domain having the amino acid sequenceof SEQ ID NO:20 and/or a VL domain having the amino acid sequence of SEQID NO:28. In one aspect an antibody that binds to C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope)comprises a VH domain having the amino acid sequence of SEQ ID NO:21and/or a VL domain having the amino acid sequence of SEQ ID NO:28. Inone aspect an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH domain having the amino acid sequence of SEQ ID NO:22 and/or a VLdomain having the amino acid sequence of SEQ ID NO:28. In one aspect anantibody that binds to C10orf54 (e.g., C10orf54 polypeptide, C10orf54polypeptide fragment, C10orf54 epitope) comprises a VH domain having theamino acid sequence of SEQ ID NO:23 and/or a VL domain having the aminoacid sequence of SEQ ID NO:28. In one aspect an antibody that binds toC10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope) comprises a VH domain having the amino acid sequenceof SEQ ID NO:20 and/or a VL domain having the amino acid sequence of SEQID NO:29. In one aspect an antibody that binds to C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope)comprises a VH domain having the amino acid sequence of SEQ ID NO:21and/or a VL domain having the amino acid sequence of SEQ ID NO:29. Inone aspect an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH domain having the amino acid sequence of SEQ ID NO:22 and/or a VLdomain having the amino acid sequence of SEQ ID NO:29. In one aspect anantibody that binds to C10orf54 (e.g., C10orf54 polypeptide, C10orf54polypeptide fragment, C10orf54 epitope) comprises a VH domain having theamino acid sequence of SEQ ID NO:23 and/or a VL domain having the aminoacid sequence of SEQ ID NO:29.

In some embodiments, antibodies that bind to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprise aVH domain having the amino acid sequence of SEQ ID NOS:12, 13, 14 or 15and/or a VL domain having the amino acid sequence of SEQ ID NO:24 or 25.Accordingly, in one aspect an antibody that binds to C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope)comprises a VH domain having the amino acid sequence of SEQ ID NO:12and/or a VL domain having the amino acid sequence of SEQ ID NO:24. Inone aspect an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH domain having the amino acid sequence of SEQ ID NO:13 and/or a VLdomain having the amino acid sequence of SEQ ID NO:24. In one aspect anantibody that binds to C10orf54 (e.g., C10orf54 polypeptide, C10orf54polypeptide fragment, C10orf54 epitope) comprises a VH domain having theamino acid sequence of SEQ ID NO:14 and/or a VL domain having the aminoacid sequence of SEQ ID NO:24. In one aspect an antibody that binds toC10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope) comprises a VH domain having the amino acid sequenceof SEQ ID NO:15 and/or a VL domain having the amino acid sequence of SEQID NO:24. In one aspect an antibody that binds to C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope)comprises a VH domain having the amino acid sequence of SEQ ID NO:12and/or a VL domain having the amino acid sequence of SEQ ID NO:25. Inone aspect an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH domain having the amino acid sequence of SEQ ID NO:13 and/or a VLdomain having the amino acid sequence of SEQ ID NO:25. In one aspect anantibody that binds to C10orf54 (e.g., C10orf54 polypeptide, C10orf54polypeptide fragment, C10orf54 epitope) comprises a VH domain having theamino acid sequence of SEQ ID NO:14 and/or a VL domain having the aminoacid sequence of SEQ ID NO:25. In one aspect an antibody that binds toC10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope) comprises a VH domain having the amino acid sequenceof SEQ ID NO:15 and/or a VL domain having the amino acid sequence of SEQID NO:25.

In some embodiments, antibodies that bind to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprise aVH domain having the amino acid sequence of SEQ ID NOS:16, 17, 18 or 19and/or a VL domain having the amino acid sequence of SEQ ID NO:26 or 27.Accordingly, in one aspect an antibody that binds to C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope)comprises a VH domain having the amino acid sequence of SEQ ID NO:16and/or a VL domain having the amino acid sequence of SEQ ID NO:26. Inone aspect an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH domain having the amino acid sequence of SEQ ID NO:17 and/or a VLdomain having the amino acid sequence of SEQ ID NO:26. In one aspect anantibody that binds to C10orf54 (e.g., C10orf54 polypeptide, C10orf54polypeptide fragment, C10orf54 epitope) comprises a VH domain having theamino acid sequence of SEQ ID NO:18 and/or a VL domain having the aminoacid sequence of SEQ ID NO:26. In one aspect an antibody that binds toC10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope) comprises a VH domain having the amino acid sequenceof SEQ ID NO:19 and/or a VL domain having the amino acid sequence of SEQID NO:26. In one aspect an antibody that binds to C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope)comprises a VH domain having the amino acid sequence of SEQ ID NO:16and/or a VL domain having the amino acid sequence of SEQ ID NO:27. Inone aspect an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH domain having the amino acid sequence of SEQ ID NO:17 and/or a VLdomain having the amino acid sequence of SEQ ID NO:27. In one aspect anantibody that binds to C10orf54 (e.g., C10orf54 polypeptide, C10orf54polypeptide fragment, C10orf54 epitope) comprises a VH domain having theamino acid sequence of SEQ ID NO:18 and/or a VL domain having the aminoacid sequence of SEQ ID NO:27. In one aspect an antibody that binds toC10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope) comprises a VH domain having the amino acid sequenceof SEQ ID NO:19 and/or a VL domain having the amino acid sequence of SEQID NO:27.

In certain embodiments, antibodies provided herein that bind to aC10orf54 epitope comprise a VH region having a VH CDR1, VH CDR2, and/orVH CDR3, that have an amino acid sequence identified in Tables 5-7below; and/or a VL region having VL CDR1, VL CDR 2 and/or VL CDR3 thathave an amino acid sequence identified in Tables 5-7 below.

TABLE 5 Amino Acid Sequences derived from Murine 175A Antibody.175A HUMANIZED ANTIBODY SEQUENCE: HEAVY CHAIN175A-huVH1a Variable RegionQVQLVQSGAEVKKPGASVKVSCKASGYTFSTHWIEWVRQAPGQGLEWMGEILPGSGSTSYNEKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARWLLYYYAMDYWGQGTLVTVSS (SEQ ID NO: 20) 175A-huVH1a VH FR1QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 51) QVQLVQSGAEVKKPGASVK ISCKAS (SEQ ID NO: 105) 175A-huVH1a VH CDR1 GYTFSTHWIE (SEQ ID NO: 36)175A-huVH1a VH FR2 WVRQAPGQGLEWMG (SEQ ID NO: 52) WVRQAPGQGLEW IG (SEQ ID NO: 106) 175A-huVH1a VH CDR2 EILPGSGSTSYNEKFKG (SEQ ID NO: 37)EILPGSGSTSY Q EKFKG (SEQ ID NO: 101) EILPGSGSTSY SEKFKG (SEQ ID NO: 102) EILPGSGSTSY D EKFKG (SEQ ID NO: 103) EILPGSGSTSYA EKFKG (SEQ ID NO: 104) 175A-huVH1a VH FR3RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 53) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 107) RVT FTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 108) RVTMT ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 109) R A T FTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 110) RVT F T ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 111) R A TMT ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 112) R A T F T ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 113) 175A-huVH1a VH CDR3WLLYYYAMDY (SEQ ID NO: 38) 175A-huVH1a VH FR4WGQGTLVTVSS (SEQ ID NO: 54) 175A-huVH1b Variable RegionQVQLVQSGAEVKKPGASVKVSCKASGYTFSTHWIEWVRQAPGQGLEWMGEILPGSGSTSYAQKLQGRVTMTTDISTSTAYMELRSLRSDDTAVYYCARWLLYYYAMDYWGQGTLVTVSS (SEQ ID NO: 21) 175A-huVH1b VH FR1QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 51) QVQLVQSGAEVKKPGASVK ISCKAS (SEQ ID NO: 105) 175A-huVH1b VH CDR1 GYTFSTHWIE (SEQ ID NO: 36)175A-huVH1b VH FR2 WVRQAPGQGLEWMG (SEQ ID NO: 52) WVRQAPGQGLEW IG (SEQ ID NO: 106) 175A-huVH1b VH CDR2*EILPGSGSTSYAQKLQG (SEQ ID NO: 50) EILPGSGSTSYAQK F QG (SEQ ID NO: 114)175A-huVH1b VH FR3 RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 53) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 107) RVT FTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 108) RVTMT ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 109) R A T FTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 110) RVT F T ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 111) R A TMT ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 112) R A T F T ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 113) 175A-huVH1b VH CDR3WLLYYYAMDY (SEQ ID NO: 38) 175A-huVH1b VH FR4WGQGTLVTVSS (SEQ ID NO: 54) 175A-huVH3a Variable RegionEVQLVESGGGLVQPGGSLRLSCAASGYTFSTHWIEWVRQAPGKGLEWVSEILPGSGSTSYNEKFKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARWLLYYYAMDYWGQGTLVTVSS(SEQ ID NO: 22) 175A-huVH3a VH FR1EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 55) EVQLV QSGGGLVQPGGSLRLSCAAS (SEQ ID NO: 115) EVQLVESGGGLVQPGGS VRLSCAAS (SEQ ID NO: 116) EVQLVESGGGLVQPGGSLR I SCAAS (SEQ ID NO: 117)EVQLV Q SGGGLVQPGGS V RLSCAAS (SEQ ID NO: 118) EVQLVESGGGLVQPGGS V R ISCAAS (SEQ ID NO: 119) EVQLV Q SGGGLVQPGGSLR I SCAAS (SEQ ID NO: 120)EVQLV Q SGGGLVQPGGS V R I SCAAS (SEQ ID NO: 121) 175A-huVH3a VH CDR1GYTFSTHWIE (SEQ ID NO: 36) 175A-huVH3a VH FR2WVRQAPGKGLEWVS (SEQ ID NO: 56) WVRQAPGKGLEW I S (SEQ ID NO: 122)WVRQAPGKGLEWV G  (SEQ ID NO: 123) WVRQAPGKGLEW IG  (SEQ ID NO: 124)175A-huVH3a VH CDR2 EILPGSGSTSYNEKFKG (SEQ ID NO: 37) EILPGSGSTSY QEKFKG (SEQ ID NO: 101) EILPGSGSTSY S EKFKG (SEQ ID NO: 102) EILPGSGSTSYD EKFKG (SEQ ID NO: 103) EILPGSGSTSY A EKFKG (SEQ ID NO: 104)175A-huVH3a VH FR3 RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 57) R ATISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 125) RFT FSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 126) RFTIS ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 127) RFTISRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 128) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 129) RFTISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 130) RFTISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 131) R A T FSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 132) R A TIS ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 133) R A TISRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 134) R A TISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 135) R A TISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 136) R A TISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 137) RFT F S ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 138) RFT F SRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 139) RFT F SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 140) RFT FSRDNAKNSLYMQMNSLRAEDTAVYYCAR (SEQ ID NO: 141) RFT FSRDNAKNSLYLQLNSLRAEDTAVYYCAR (SEQ ID NO: 142) RFTIS A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 143) RFTIS A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 144) RFTIS A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 145) RFTIS A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 146) RFTISRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 147) RFTISRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 148) RFTISRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 149) RFTISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 150) RFTISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 151) RFTISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 152) R A T F S ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 153) R A T F SRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 154) R A T F SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 155) R A T F SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 156) R A T F SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 157) R A TIS A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 158) R A TIS A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 159) R A TIS A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 160) R A TIS A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 161) R A TISRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 162) R A TISRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 163) R A TISRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 164) R A TISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 165) R A TISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 166) R A TISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 167) RFT F SAD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 168) RFT F SADNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 169) RFT F SADNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 170) RFT F SADNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 171) RFT F SRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 172) RFT F SRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 173) RFT F SRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 174) RFT F SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 175) RFT F SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 176) RFT F SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 177) RFTISAD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 178) RFTISAD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 179) RFTISAD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 180) RFTISADNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 181) RFTISADNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 182) RFTISADNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 183) RFTISRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 184) RFTISRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 185) RFTISRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 186) RFTISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 187) RAT F SAD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 188) R A T F SADNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 189) R A T F SADNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 190) R A T F SADNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 191) R A T F SRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 192) R A T F SRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 193) R A T F SRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 194) R A T F SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 195) R A T F SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 196) R A T F SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 197) R A TIS A D T AKN ALYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 198) R A TIS A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 199) R A TIS A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 200) R A TIS A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 201) R A TIS A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 202) R A TIS A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 203) R A TISRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 204) R A TISRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 205) R A TISRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 206) R A TISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 207) RFT F S A D T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 208) RFT F S A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 209) RFT F S A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 210) RFT F S A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 211) RFT F S A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 212) RFT F S A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 213) RFT F SRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 214) RFT F SRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 215) RFT F SRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 216) RFT F SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 217) RFTISAD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 218) RFTIS A D T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 219) RFTIS A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 220) RFTIS A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 221) RFTISRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 222) R A T F S A D T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 223) R A T F S A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 224) R A T F S A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 225) R A T F S A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 226) R A T F S A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 227) R A T F S A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 228) R A T F SRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 229) R A T F SRD T AKNS A YLQ LNSLRAEDTAVYYCAR CSEQ ID NO: 230) R A T F SRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 231) R A T F SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 232) R A TIS A D T AKNALY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 233) R A TIS A D T AKN A LYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 234) R A TIS A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 235) R A TIS A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 236) R A TISRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 237) RFT F S A D T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 238) RFT F S A D T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 239) RFT F S A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 240) RFT F S A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 241) RFT F SRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 242) RFTIS A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 243) R A T F S A D T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 244) R A T F S A D T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 245) R A T F S A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 246) R A T F S A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 247) R A T F SRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 248) R A TIS A D T AKNALY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 249) RFT F S A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 250) R A T F S A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 251) 175A-huVH3a VH CDR3WLLYYYAMDY (SEQ ID NO: 38) 175A-huVH3a VH FR4WGQGTLVTVSS (SEQ ID NO: 54) 175A-huVH3b Variable RegionEVQLVESGGGLVQPGGSLRLSCAASGYTFSTHWIEWVRQAPGKGEWVSEILPGSGSTSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARWLLYYYAMDYWGQGTLVTVSS(SEQ ID NO: 23) 175A-huVH3b VH FR1EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 55) EVQLV QSGGGLVQPGGSLRLSCAAS (SEQ ID NO: 115) EVQLVESGGGLVQPGGS VRLSCAAS (SEQ ID NO: 116) EVQLVESGGGLVQPGGSLR I SCAAS (SEQ ID NO: 117)EVQLV Q SGGGLVQPGGS V RLSCAAS (SEQ ID NO: 118) EVQLVESGGGLVQPGGS V R ISCAAS (SEQ ID NO: 119) EVQLV Q SGGGLVQPGGSLR I SCAAS (SEQ ID NO: 120)EVQLV Q SGGGLVQPGGS V R I SCAAS (SEQ ID NO: 121) 175A-huVH3b VH CDR1GYTFSTHWIE (SEQ ID NO: 36) 175A-huVH3b VH FR2WVRQAPGKGLEWVS (SEQ ID NO: 56) WVRQAPGKGLEW I S (SEQ ID NO: 122)WVRQAPGKGLEWV G  (SEQ ID NO: 123) WVRQAPGKGLEW IG  (SEQ ID NO: 124)175A-huVH3b VH CDR2* EILPGSGSTSYADSVKG (SEQ ID NO: 99) EILPGSGSTSYADS FKG (SEQ ID NO: 100) 175A-huVH3b VH FR3RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 57) R ATISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 125) RFT FSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 126) RFTIS ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 127) RFTISRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 128) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 129) RFTISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 130) RFTISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 131) R A T FSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 132) R A TIS ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 133) R A TISRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 134) R A TISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 135) R A TISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 136) R A TISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 137) RFT F S ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 138) RFT F SRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 139) RFT F SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 140) RFT FSRDNAKNSLYMQMNSLRAEDTAVYYCAR (SEQ ID NO: 141) RFT FSRDNAKNSLYLQLNSLRAEDTAVYYCAR (SEQ ID NO: 142) RFTIS A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 143) RFTIS A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 144) RFTIS A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 145) RFTIS A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 146) RFTISRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 147) RFTISRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 148) RFTISRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 149) RFTISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 150) RFTISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 151) RFTISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 152) R A T F S ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 153) R A T F SRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 154) R A T F SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 155) R A T F SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 156) R A T F SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 157) R A TIS A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 158) R A TIS A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 159) R A TIS A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 160) R A TIS A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 161) R A TISRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 162) R A TISRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 163) R A TISRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 164) R A TISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 165) R A TISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 166) R A TISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 167) RFT F SAD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 168) RFT F SADNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 169) RFT F SADNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 170) RFT F SADNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 171) RFT F SRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 172) RFT F SRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 173) RFT F SRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 174) RFT F SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 175) RFT F SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 176) RFT F SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 177) RFTISAD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 178) RFTISAD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 179) RFTISAD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 180) RFTISADNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 181) RFTISADNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 182) RFTISADNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 183) RFTISRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 184) RFTISRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 185) RFTISRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 186) RFTISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 187) RAT F SAD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 188) R A T F SADNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 189) R A T F SADNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 190) R A T F SADNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 191) R A T F SRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 192) R A T F SRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 193) R A T F SRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 194) R A T F SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 195) R A T F SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 196) R A T F SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 197) R A TIS A D T AKN ALYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 198) R A TIS A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 199) R A TIS A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 200) R A TIS A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 201) R A TIS A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 202) R A TIS A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 203) R A TISRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 204) R A TISRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 205) R A TISRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 206) R A TISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 207) RFT F S A D T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 208) RFT F S A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 209) RFT F S A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 210) RFT F S A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 211) RFT F S A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 212) RFT F S A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 213) RFT F SRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 214) RFT F SRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 215) RFT F SRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 216) RFT F SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 217) RFTISAD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 218) RFTIS A D T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 219) RFTIS A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 220) RFTIS A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 221) RFTISRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 222) R A T F S A D T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 223) R A T F S A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 224) R A T F S A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 225) R A T F S A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 226) R A T F S A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 227) R A T F S A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 228) R A T F SRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 229) R A T F SRD T AKNS A YLQ LNSLRAEDTAVYYCAR CSEQ ID NO: 230) R A T F SRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 231) R A T F SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 232) R A TIS A D T AKNALY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 233) R A TIS A D T AKN A LYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 234) R A TIS A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 235) R A TIS A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 236) R A TISRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 237) RFT F S A D T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 238) RFT F S A D T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 239) RFT F S A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 240) RFT F S A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 241) RFT F SRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 242) RFTIS A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 243) R A T F S A D T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 244) R A T F S A D T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 245) R A T F S A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 246) R A T F S A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 247) R A T F SRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 248) R A TIS A D T AKNALY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 249) RFT F S A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 250) R A T F S A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 251) 175A-huVH3b VH CDR3WLLYYYAMDY (SEQ ID NO: 38) 175A-huVH3b V FR4 WGQGTLVTVSS (SEQ ID NO: 54)175A-huVK2 VL Variable Region DIVMTQSPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKLSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHFPYTFGQGTKLEIK (SEQ ID NO: 28)175A-huVK2 VL FR1 DIVMTQSPLSLPVTPGEPASISC (SEQ ID NO: 75) D VVMTQSPLSLPVTPGEPASISC (SEQ ID NO: 252) 175A-huVK2 VL CDR1RSSQSIVHSNGNTYLE (SEQ ID NO: 45) RSSQSIVHS Q GNTYLE (SEQ ID NO: 253)RSSQSIVHS S GNTYLE (SEQ ID NO: 254) RSSQSIVHS A GNTYLE (SEQ ID NO: 255)RSSQSIVHSNG Q TYLE (SEQ ID NO: 256) RSSQSIVHSNG S TYLE (SEQ ID NO: 257)RSSQSIVHSNG A TYLE (SEQ ID NO: 258) RSSQSIVHSNG D TYLE (SEQ ID NO: 259)RSSQSIVHS Q G Q TYLE (SEQ ID NO: 260) RSSQSIVHS Q G STYLE (SEQ ID NO: 261) RSSQSIVHS Q G A TYLE (SEQ ID NO: 262) RSSQSIVHS QG D TYLE (SEQ ID NO: 263) RSSQSIVHS S G Q TYLE (SEQ ID NO: 264)RSSQSIVHS S G S TYLE (SEQ ID NO: 265) RSSQSIVHS S G ATYLE (SEQ ID NO: 266) RSSQSIVHS S G D TYLE (SEQ ID NO: 267) RSSQSIVHS AG Q TYLE (SEQ ID NO: 268) RSSQSIVHS A G S TYLE (SEQ ID NO: 269)RSSQSIVHS A G A TYLE (SEQ ID NO: 270) RSSQSIVHS A G DTYLE (SEQ ID NO: 271) 175A-huVK2 VL FR2 WYLQKPGQSPQLLIY (SEQ ID NO: 76)175A-huVK2 VL CDR2 KLSNRFS (SEQ ID NO: 46) KLSQRFS (SEQ ID NO: 272)KLSSRFS (SEQ ID NO: 273) KLSARFS (SEQ ID NO: 274)KLSDRFS (SEQ ID NO: 275) 175A-huVK2 VL FR3GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC (SEQ ID NO: 77)GVPDRFSGSGSGTDFTLKISRVEAED L GVYYC (SEQ ID NO: 276) 175A-huVK2 VL CDR3FQGSHFPYT (SEQ ID NO: 47) 175A-huVK2 VL FR4 FGQGTKLEIK (SEQ ID NO: 78)175A-huVK1 Variable RegionDIQMTQSPSSLSASVGDRVTITCRSSQSIVHSNGNTYLEWYQQKPGKAPKWYKLSNRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQGSHFPYTEGQGTKLEIK (SEQ ID NO: 29)175A-huVK1 VL FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 79)DVQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 277) DIQMTQSPSSLS VSVGDRVTITC (SEQ ID NO: 278) DIQMTQSPSSLSASVGDR A TITC (SEQ ID NO: 279) DV QMTQSPSSLS V SVGDRVTITC (SEQ ID NO: 280) D V QMTQSPSSLSASVGDR ATITC (SEQ ID NO: 281) DIQMTQSPSSLS V SVGDR A TITC CSEQ ID NO: 282) D VQMTQSPSSLS V SVGDR A TITC (SEQ ID NO: 283) 175A-huVK1 VL CDR1RSSQSIVHSNGNTYLE (SEQ ID NO: 45) RSSQSIVHS Q GNTYLE (SEQ ID NO: 253)RSSQSIVHS S GNTYLE (SEQ ID NO: 254) RSSQSIVHS A GNTYLE (SEQ ID NO: 255)RSSQSIVHSNG Q TYLE (SEQ ID NO: 256) RSSQSIVHSNG S TYLE (SEQ ID NO: 257)RSSQSIVHSNG A TYLE (SEQ ID NO: 258) RSSQSIVHSNG D TYLE (SEQ ID NO: 259)RSSQSIVHS Q G Q TYLE (SEQ ID NO: 260) RSSQSIVHS Q G STYLE (SEQ ID NO: 261) RSSQSIVHS Q G A TYLE (SEQ ID NO: 262) RSSQSIVHS QG D TYLE (SEQ ID NO: 263) RSSQSIVHS S G Q TYLE (SEQ ID NO: 264)RSSQSIVHS S G S TYLE (SEQ ID NO: 265) RSSQSIVHS S G ATYLE (SEQ ID NO: 266) RSSQSIVHS S G D TYLE (SEQ ID NO: 267) RSSQSIVHS AG Q TYLE (SEQ ID NO: 268) RSSQSIVHS A G S TYLE (SEQ ID NO: 269)RSSQSIVHS A G A TYLE (SEQ ID NO: 270) RSSQSIVHS A G DTYLE (SEQ ID NO: 271) 175A-huVEK1 VL FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 80)WYQQKPGK S PKLLIY (SEQ ID NO: 284) 175A-huVK1 VL CDR2KLSNRFS (SEQ ID NO: 46) KLS Q RFS (SEQ ID NO: 272) KLS SRFS (SEQ ID NO: 273) KLS A RFS (SEQ ID NO: 274) KLS DRFS (SEQ ID NO: 275) 175A-huVK1 VL FR3GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 81) GVPSRFSGSGSGTDFTLTISS VQPEDFATYYC (SEQ ID NO: 285) GVPSRFSGSGSGTDFTLTISSLQPED LATYYC (SEQ ID NO: 286) GVPSRFSGSGSGTDFTLTISSLQPEDF GTYYC (SEQ ID NO: 287) GVPSRFSGSGSGTDFTLTISS V QPED LATYYC (SEQ ID NO: 288) GVPSRFSGSGSGTDFTLTISS V QPEDF GTYYC (SEQ ID NO: 289) GVPSRFSGSGSGTDFTLTISSLQPED LGTYYC (SEQ ID NO: 290) GVPSRFSGSGSGTDFTLTISS V QPED LGTYYC (SEQ ID NO: 291) 175A-huVK1 VL CDR3 FQGSHFPYT (SEQ ID NO: 47)175A-huVK1 VL FR4 FGQGTKLEIK (SEQ ID NO: 78) *Amino acid positionnumbering as in Kabat.

TABLE 6 Amino Acid Sequences derived from Murine 76E1 Antibody.76E1 HUMANIZED ANTIBODY SEQUENCE: HEAVY CHAIN 76E1 huVH1a VH FR1QVQLVQSGAEVKKPGASVKVSCKASGYSFTGYNMNWVRQAPGQGLEWMGNIDPYYDYTSYNLKFKDRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARSTMITPFDYWGQGTLVTVSS(SEQ ID NO: 12) 76E1-huVH1a VH FR1QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 51) QVQLVQSGAEVKKPGASVK ISCKAS (SEQ ID NO: 105) 76E1-huVH1a VH CDR1 GYSFTGYNMN (SEQ ID NO: 30)GYSFTGY Q MN (SEQ ID NO: 59) GYSFTGY S MN (SEQ ID NO: 60) GYSFTGY DMN (SEQ ID NO: 61) GYSFTGY A MN (SEQ ID NO: 62) 76E1-huVH1a VH FR2WVRQAPGQGLEWMG (SEQ ID NO: 52) WVRQAPGQ S LEWMG (SEQ ID NO: 63)WVRQAPGQGLEW I G (SEQ ID NO: 106) WVRQAPGQ S LEW I G (SEQ ID NO: 64)76E1-huVH1a VH CDR2 NIDPYYDYTSYNLKFKD (SEQ ID NO: 31) NI EPYYDYTSYNLKFKD (SEQ ID NO: 65) NI S PYYDYTSYNLKFKD (SEQ ID NO: 66) NI APYYDYTSYNLKFKD (SEQ ID NO: 67) NIDPYYDYTSY Q LKFKD (SEQ ID NO: 68)NIDPYYDYTSY S LKFKD (SEQ ID NO: 69) NIDPYYDYTSY D LKFKD (SEQ ID NO: 70)NIDPYYDYTSY A LKFKD (SEQ ID NO: 71) NI E PYYDYTSY QLKFKD (SEQ ID NO: 72) NI E PYYDYTSY S LKFKD (SEQ ID NO: 73) NI EPYYDYTSY D LKFKD (SEQ ID NO: 74) NI E PYYDYTSY A LKFKD (SEQ ID NO: 83)NI S PYYDYTSY Q LKFKD (SEQ ID NO: 84) NI S PYYDYTSY SLKFKD (SEQ ID NO: 85) NI S PYYDYTSY D LKFKD (SEQ ID NO: 86) NI SPYYDYTSY A LKFKD (SEQ ID NO: 87) NI A PYYDYTSY Q LKFKD (SEQ ID NO: 88)NI A PYYDYTSY S LKFKD (SEQ ID NO: 89) NI A PYYDYTSY DLKFKD (SEQ ID NO: 90) NI A PYYDYTSY A LKFKD (SEQ ID NO: 95)76E1-huVH1a VH FR3 RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 53) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 107) RVT LTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 96) RVTMT VDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 97) RVTMTTD KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 98) RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAT  (SEQ ID NO: 292) R A T LTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 293) R A TMT VDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 294) R A TMTTD KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 295) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 296) RVT L T VDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 297) RVT L TTD KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 298) RVT LTTDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 299) RVTMT V D KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 300) RVTMT VDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 301) RVTMTTD KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 302) R A T L T VDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 303) R A T L TTD KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 304) R A T LTTDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 305) R A TMT V D KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 306) R A TMT VDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 307) R A TMTTD KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 308) RVT L T V D KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 309) RVT L T VDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 310) RVT L TTD KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 311) RVTMT V D KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 312) R A T L T V D KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 313) R A T L T VDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 314) R A T L TTD KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 315) R A TMT V D KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 316) RVT L T V D KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 317) R A T L T V D KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 318) 76E1-huVH1a VH CDR3STMITPFDY (SEQ ID NO: 32) ST L ITPFDY (SEQ ID NO: 319) 6E1-huVH1a VH FR4WGQGTLVTVSS (SEQ ID NO: 54) WGQGTL L TVSS (SEQ ID NO: 320)76E1-huVH1b Variable RegionQVQLVQSGAEVKKPGASVKVSCKASGYSFTGYNMNWVRQAPGQGLEWMGNIDPYYDYTSYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARSTMITPFDYWGQGTLVTVSS(SEQ ID NO: 13) 76E1-huVH1b VH FR1QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 51) QVQLVQSGAEVKKPGASVK ISCKAS (SEQ ID NO: 105) 76E1-huVH1b VH CDR1 GYSFTGYNMN (SEQ ID NO: 30)GYSFTGY Q MN (SEQ ID NO: 59) GYSFTGY S MN (SEQ ID NO: 60) GYSFTGY DMN (SEQ ID NO: 61) GYSFTGY A MN (SEQ ID NO: 62) 76E1-huVH1b VH FR2WVRQAPGQGLEWMG (SEQ ID NO: 52) WVRQAPGQ S LEWMG (SEQ ID NO: 63)WVRQAPGQGLEW I G (SEQ ID NO: 106) WVRQAPGQ S LEW I G (SEQ ID NO: 64)76E1-huVH1b VH CDR2* NIDPYYDYTSYAQKLQG (SEQ ID NO: 321) NIDPYYDYTSYAQK FQG (SEQ ID NO: 322) 76E1-huVH1b VH FR3RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 53) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 107) RVT LTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 96) RVTMT VDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 97) RVTMTTD KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 98) RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAT  (SEQ ID NO: 292) R A T LTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 293) R A TMT VDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 294) R A TMTTD KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 295) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 296) RVT L T VDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 297) RVT L TTD KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 298) RVT LTTDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 299) RVTMT V D KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 300) RVTMT VDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 301) RVTMTTD KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 302) R A T L T VDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 303) R A T L TTD KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 304) R A T LTTDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 305) R A TMT V D KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 306) R A TMT VDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 307) R A TMTTD KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 308) RVT L T V D KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 309) RVT L T VDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 310) RVT L TTD KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 311) RVTMT V D KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 312) R A T L T V D KSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 313) R A T L T VDTSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 314) R A T L TTD KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 315) R A TMT V D KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 316) RVT L T V D KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 317) R A T L T V D KSTSTAYMELRSLRSDDTAVYYCA T  (SEQ ID NO: 318) 76E1-huVH1b VH CDR3STMITPFDY (SEQ ID NO: 32) STLITPFDY (SEQ ID NO: 319) 76E1-huVH1b VH FR4WGQGTLVTVSS (SEQ ID NO: 54) WGQGTLLTVSS (SEQ ID NO: 320)76E1-huVH3a Variable RegionEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYNMNWVRQAPGKGLEWVSNSNIDPYYDYTSYNLKFKDRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARSTMITPFDYWGQGTLVTVSS(SEQ ID NO: 14) 76E1-huVH3a VH FR1EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 55) EVQLV QSGGGLVQPGGSLRLSCAAS (SEQ ID NO: 115) EVQLVESGGGLVQPGGS VRLSCAAS (SEQ ID NO: 116) EVQLVESGGGLVQPGGSLR I SCAAS (SEQ ID NO: 117)EVQLV Q SGGGLVQPGGS V RLSCAAS (SEQ ID NO: 118) EVQLVESGGGLVQPGGS V R ISCAAS (SEQ ID NO: 119) EVQLV Q SGGGLVQPGGSLR I SCAAS (SEQ ID NO: 120)EVQLV Q SGGGLVQPGGS V R I SCAAS (SEQ ID NO: 121) 76E1-huVH3a VH CDR1GYSFTGYNMN (SEQ ID NO: 30) GYSFTGY Q MN (SEQ ID NO: 59) GYSFTGY SMN (SEQ ID NO: 60) GYSFTGY D MN (SEQ ID NO: 61) GYSFTGY AMN (SEQ ID NO: 62) 76E1-huVH3a VH FR2 WVRQAPGKGLEWVS (SEQ ID NO: 56)WVRQAPGK S LEWVS (SEQ ID NO: 323) WVRQAPGKGLEW I S (SEQ ID NO: 122)WVRQAPGKGLEWV G  (SEQ ID NO: 123) WVRQAPGK S LEW I S (SEQ ID NO: 324)WVRQAPGK S LEWV G  (SEQ ID NO: 325) WVRQAPGKGLEW IG  (SEQ ID NO: 124)WVRQAPGK S LEW IG  (SEQ ID NO: 326) 76E1-huVH3a VH CDR2NIDPYYDYTSYNLKFKD (SEQ ID NO: 31) NI E PYYDYTSYNLKFKD (SEQ ID NO: 65) NIS PYYDYTSYNLKFKD (SEQ ID NO: 66) NI A PYYDYTSYNLKFKD (SEQ ID NO: 67)NIDPYYDYTSY Q LKFKD (SEQ ID NO: 68) NIDPYYDYTSY S LKFKD (SEQ ID NO: 69)NIDPYYDYTSY D LKFKD (SEQ ID NO: 70) NIDPYYDYTSY A LKFKD (SEQ ID NO: 71)NI E PYYDYTSY Q LKFKD (SEQ ID NO: 72) NI E PYYDYTSY SLKFKD (SEQ ID NO: 73) NI E PYYDYTSY D LKFKD (SEQ ID NO: 74) NI EPYYDYTSY A LKFKD (SEQ ID NO: 83) NI S PYYDYTSY Q LKFKD (SEQ ID NO: 84)NI S PYYDYTSY S LKFKD (SEQ ID NO: 85) NI S PYYDYTSY DLKFKD (SEQ ID NO: 86) NI S PYYDYTSY A LKFKD (SEQ ID NO: 87) NI APYYDYTSY Q LKFKD (SEQ ID NO: 88) NI A PYYDYTSY S LKFKD (SEQ ID NO: 89)NI A PYYDYTSY D LKFKD (SEQ ID NO: 90) NI A PYYDYTSY ALKFKD (SEQ ID NO: 95) 76E1-huVH3a VH FR3RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 57) R ATISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 327) RFT LSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 328) RFTIS VDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 329) RFTISRD KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 330) RFTISRDNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 331) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 332) RFTISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 333) RFTISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 334) RFTISRDNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 335) R A T L SRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 336)R A TIS V DNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 337) R A TISRD KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 338) R A TISRDNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 339) R A TISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 340) R A TISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 341) R A TISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 342) R A TISRDNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 343) RFT L S V DNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 344)RFT L SRD K AKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 345) RFT L SRDNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 346) RFT L SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 347) RFT L SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 348) RFT L SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 349) RFT L SRDNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 350) RFTIS V D K AKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 351)RFTIS V DNAK S SLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 352) RFTIS V DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 353) RFTIS V DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 354) RFTIS V DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 355) RFTIS V DNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 356) RFTISRD K AK S SLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 357)RFTISRD K AKNS A YLQMNSLRAEDTAVYYCAR (SEQ ID NO: 358) RFTISRD K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 359) RFTISRD K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 360) RFTISRD K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 361) RFTISRDNAK S S A YLQMNSLRAEDTAVYYCAR (SEQ ID NO: 362)RFTISRDNAK S SLY M QMNSLRAEDTAVYYCAR (SEQ ID NO: 363) RFTISRDNAK S SLYLQL NSLRAEDTAVYYCAR (SEQ ID NO: 364) RFTISRDNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 365) RFTISRDNAKNS A Y M QMNSLRAEDTAVYYCAR (SEQ ID NO: 366)RFTISRDNAKNS A YLQ L NSLRAEDTAVYYCAR (SEQ ID NO: 367) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 368) RFTISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 369) RFTISRDNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 370) RFTISRDNAKNSLYLQ L NSLRAEDTAVYYCA T  (SEQ ID NO: 371)R A T L S V DNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 372) R A T L SRD KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 373) R A T L SRDNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 374) R A T L SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 375) R A T L SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 376) R A T L SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 377) R A T L SRDNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 378) R A TIS V DKAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 379)R A TIS V DNAK S SLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 380) R A TIS V DNAKNSA YLQMNSLRAEDTAVYYCAR (SEQ ID NO: 381) R A TIS V DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 382) R A TIS V DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 383) R A TIS V DNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 384) R A TISRD K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 385) R A TISRD K AKNS AYLQMNSLRAEDTAVYYCAR CSEQ ID NO: 386) R A TISRD K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 387) R A TISRD K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 388) R A TISRD K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 389) R A TISRDNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 390) R A TISRDNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 391) R A TISRDNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 392) R A TISRDNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 393) R A TISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 394) R A TISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 395) R A TISRDNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 396) R A TISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 397) R A TISRDNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 398) R A TISRDNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 399) RFT L S V D KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 400) RFT L S V DNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 401) RFT L S V DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 402) RFT L S V DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 403) RFT L S V DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 404) RFT L S V DNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 405) RFT L SRD K A SNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 406) RFT L SRDKAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 407) RFT L SRDKAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 408) RFT L SRDKAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 409) RFT L SRDKAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 410) RFT L SRDNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 411) RFT L SRDNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 412) RFT L SRDNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 413) RFT L SRDNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 414) RFT L SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 415) RFT L SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 416) RFT L SRDNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 417) RFT L SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 418) RFT L SRDNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 419) RFT L SRDNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 420) RFTIS V D K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 421) RFTIS V D K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 422) RFTIS V D K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 423) RFTIS V D K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 424) RFTIS V D K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 425) RFTIS V DNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 426) RFTIS V DNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 427) RFTIS V DNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 428) RFTIS V DNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 429) RFTIS V DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 430) RFTIS V DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 431) RFTIS V DNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 432) RFTIS V DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 433) RFTIS V DNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 434) RFTIS V DNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 435) RFTISRD K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 436) RFTISRD K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 437) RFTISRD K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 438) RFTISRD K AK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 439) RFTISRD K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 440) RFTISRD K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 441) RFTISRD K AKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 442) RFTISRD K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 443) RFTISRD K AKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 444) RFTISRD K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 445) RFTISRDNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 446) RFTISRDNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 447) RFTISRDNAK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 448) RFTISRDNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 449) RFTISRDNAK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 450) RFTISRDNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 451) RFTISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 452) RFTISRDNAKNS A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 453) RFTISRDNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 454) RFTISRDNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 455) R A T L S V D KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 456) R A T L S V DNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 457) R A T L S V DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 458) R A T L S V DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 459) R A T L S V DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 460) R A T L S V DNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 461) R A T L SRD K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 462) R A T L SRD K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 463) R A T L SRD K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 464) R A T L SRD K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 465) R A T L SRD K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 466) R A T L SRDNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 467) R A T L SRDNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 468) R A T L SRDNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 469) R A T L SRDNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 470) R A T L SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 471) R A T L SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 472) R A T L SRDNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 473) R A T L SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 474) R A T L SRDNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 475) R A T L SRDNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 476) R A TIS V D K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 477) R A TIS V D K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 478) R A TIS V D K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 479) R A TIS V D K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 480) R A TIS V D K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 481) R A TIS V DNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 482) R A TIS V DNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 483) R A TIS V DNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 484) R A TIS V DNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 485) R A TIS V DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 486) R A TIS V DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 487) R A TIS V DNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 488) R A TIS V DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 489) R A TIS V DNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 490) R A TIS V DNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 491) R A TISRD K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 492) R A TISRD K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 493) R A TISRD K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 494) R A TISRD K AK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 495) R A TISRD K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 496) R A TISRD K AKNSAYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 497) R A TISRD K AKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 498) R A TISRD K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 499) R A TISRD K AKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 500) R A TISRD K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 501) R A TISRDNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 502) R A TISRDNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 503) R A TISRDNAK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 504) R A TISRDNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 505) R A TISRDNAK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 506) R A TISRDNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 507) R A TISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 508) R A TISRDNAKNS A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 509) R A TISRDNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 510) R A TISRDNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 511) RFT L S V D K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 512) RFT L S V D K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 513) RFT L S V D K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 514) RFT L S V D K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 515) RFT L S V D K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 516) RFT L S V DNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 517) RFT L S V DNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 518) RFT L S V DNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 519) RFT L S V DNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 520) RFT L S V DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 521) RFT L S V DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 522) RFT L S V DNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 523) RFT L S V DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 524) RFT L S V DNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 525) RFT L S V DNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 526) RFT L SRD K A S NS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 527) RFT L SRD K A S NSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 528) RFT L SRD K A S NSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 529) RFT L SRD K A S NSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 530) RFT L SRD K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 531) RFT L SRD K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 532) RFT L SRD K AKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 533) RFT L SRD K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 534) RFT L SRD K AKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 535) RFT L SRD K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 536) RFT L SRDNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 537) RFT L SRDNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 538) RFT L SRDNAK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 539) RFT L SRDNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 540) RFT L SRDNAK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 541) RFT L SRDNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 542) RFT L SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 543) RFT L SRDNAKNS A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 544) RFT L SRDNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 545) RFT L SRDNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 546) RFTIS V D K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 547) RFTIS V D K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 548) RFTIS V D K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 549) RFTIS V D K AK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 550) RFTIS V D K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 551) RFTIS V D K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 552) RFTIS V D K AKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 553) RFTIS V D K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 554) RFTIS V D K AKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 555) RFTIS V D K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 556) RFTIS V DNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 557) RFTIS V DNAK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 558) RFTIS V DNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 559) RFTIS V DNAK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 560) RFTIS V DNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 561) RFTIS V DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 562) RFTIS V DNAKNS A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 563 RFTIS V DNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 564) RFTIS V DNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 565) RFTISRD K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 566) RFTISRD K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 567) RFTISRD K AK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 568) RFTISRD K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 569) RFTISRD K AK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 570) RFTISRD K AK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 571) RFTISRD K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 572) RFTISRD K AKNSAY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 573) RFTISRD K AKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 574) RFTISRDKAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 575) RFTISRDNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 576) RFTISRDNAK S S A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 577) RFTISRDNAK S S A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 578) RFTISRDNAK S SLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 579) RFTISRDNAKNS A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 580) R A T L S V D KASNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 581) R A T L S V D K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 582) R A T L S V D K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 583) R A T L S V D K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 584) R A T L S V D K AKNSLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 585) R A T L S V DNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 586) R A T L S V DNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 587) R A T L S V DNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 588) R A T L S V DNAK S SLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 589) R A T L S V DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 590) R A T L S V DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 591) R A T L S V DNAKNS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 592) R A T L S V DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 593) R A T L S V DNAKNSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 594) R A T L S V DNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 595) R A T L SRD K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 596) R A T L SRD K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 597) R A T L SRD K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 598) R A T L SRD K AK S SLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 599) R A T L SRD K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 600) R A T L SRD K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 601) R A T L SRD K AKNS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 602) R A T L SRD K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 603) R A T L SRD K AKNSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 604) R A T L SRD K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 605) R A T L SRDNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 606) R A T L SRDNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 607) R A T L SRDNAK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 608) R A T L SRDNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 609) R A T L SRDNAK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 610) R A T L SRDNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 611) R A T L SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 612) R A T L SRDNAKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 613) R A T L SRDNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 614) R A T L SRDNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 615) R A TIS V D K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 616) R A TIS V D K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 617) R A TIS V D K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 618) R A TIS V D K AK S SLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 619) R A TIS V D K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 620) R A TIS V D K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 621) R A TIS V D K AKNS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 622) R A TIS V D K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 623) R A TIS V D K AKNSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 624) R A TIS V D K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 625) R A TIS V DNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 626) R A TIS V DNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 627) R A TIS V DNAK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 628) R A TIS V DNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 629) R A TIS V DNAK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 630) R A TIS V DNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 631) R A TIS V DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 632) R A TIS V DNAKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 633) R A TIS V DNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 634) R A TIS V DNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 635) R A TISRD K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 636) R A TISRD K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 637) R A TISRD K AK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 638) R A TISRD K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 639) R A TISRD K AK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 640) R A TISRD K AK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 641) R A TISRD K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 642) R A TISRD K AKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 643) R A TISRD K AKNS A YLQ LNSLRAEDTAVYYCAT (SEQ ID NO: 644) R A TISRD K AKNSLY M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 645) R A TISRDNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 646) R A TISRDNAK S S A Y MQMNSLRAEDTAVYYCAT (SEQ ID NO: 647) R A TISRDNAK S SAYLQ LNSLRAEDTAVYYCAT (SEQ ID NO: 648) R A TISRDNAK S SLY M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 649) R A TISRDNAKNS A Y M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 650) RFT L S V D K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 651) RFT L S V D K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 652) RFT L S V D K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 653) RFT L S V D K AK S SLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 654) RFT L S V D K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 655) RFT L S V D K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 656) RFT L S V D K AKNS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 657) RFT L S V D K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 658) RFT L S V D K AKNSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 659) RFT L S V D K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 660) RFT L S V DNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 661) RFT L S V DNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 662) RFT L S V DNAK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 663) RFT L S V DNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 664) RFT L S V DNAK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 665) RFT L S V DNAK S SLYLQ LNSLRAEDTAVYYCAT (SEQ ID NO: 666) RFT L S V DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 667) RFT L S V DNAKNS A Y MQMNSLRAEDTAVYYCAT (SEQ ID NO: 668) RFT L S V DNAKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 669) RFT L S V DNAKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 670) RFT L SRD K A S NS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 671) RFT L SRD K A S NS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 672) RFT L SRD K A S NS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 673) RFT L SRD K A S NSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 674) RFT L SRD K A S NSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 675) RFT L SRD K A S NSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 676) RFT L SRD K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 677) RFT L SRD K AKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 678) RFT L SRD K AKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 679) RFT L SRD K AKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 680) RFT L SRDNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 681) RFT L SRDNAK S S A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 682) RFT L SRDNAK S S A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 683) RFT L SRDNAK S SLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 684) RFT L SRDNAKNS A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 685) RFTIS V D K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 686) RFTIS V D K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 687) RFTIS V D K AK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 688) RFTIS V D K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 689) RFTIS V D K AK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 690) RFTIS V D K AK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 691) RFTIS V D K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 692) RFTIS V D K AKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 693) RFTIS V D K AKNSAYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 694) RFTIS V D K AKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 695) RFTIS V DNAK S S A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 696) RFTIS V DNAK S SLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 697) RFTIS V DNAKNS A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 698) RFTISRD K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 699) RFTISRD K AK S S A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 700) RFTISRD K AK S S A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 701) RFTISRD K AK S SLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 702) RFTISRD K AKNS A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 703) RFTISRDNAK S S A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 704) R A T L S V D K A S NS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 705) R A T L S V D K A S NSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 706) R A T L S V D K A S NSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 707) R A T L S V D K A SNSLYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 708) R A T L S V D K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 709) R A T L S V D K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 710) R A T L S V D K AKNS AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 711) R A T L S V D K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 712) R A T L S V D K AKNSLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 713) R A T L S V D K AKNSLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 714) R A T L S V DNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 715) R A T L S V DNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 716) R A T L S V DNAK S S AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 717) R A T L S V DNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 718) R A T L S V DNAK S SLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 719) R A T L S V DNAK S SLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 720) R A T L S V DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 721) R A T L S V DNAKNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 722) R A T L S V DNAKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 723) R A T L S V DNAKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 724) R A T L SRD K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 725) R A T L SRD K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 726) R A T L SRD K AK S S AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 727) R A T L SRD K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 728) R A T L SRD K AK S SLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 729) R A T L SRD K AK S SLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 730) R A T L SRD K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 731) R A T L SRD K AKNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 732) R A T L SRD K AKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 733) R A T L SRD K AKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 734) R A T L SRDNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 735) R A T L SRDNAK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 736) R A T L SRDNAK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 737) R A T L SRDNAK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 738) R A T L SRDNAKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 739) R A TIS V D K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 740) R A TIS V D K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 741) R A TIS V D K AK S S AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 742) R A TIS V D K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 743) R A TIS V D K AK S SLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 744) R A TIS V D K AK S SLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 745) R A TIS V D K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 746) R A TIS V D K AKNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 747) R A TIS V D K AKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 748) R A TIS V D K AKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 749) RA TIS V DNAK S S A YMQ LNSLRAEDTAVYYCAR (SEQ ID NO: 750) R A TIS V DNAK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 751) R A TIS V DNAK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 752) R A TIS V DNAK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 753) R A TIS V DNAKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 754) R A TISRD K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 755) R A TISRD K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 756) R A TISRD K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 757) R A TISRD K AK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 758) R A TISRD K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 759) R A TISRDNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 760) RFT L S V D K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 761) RFT L S V D K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 762) RFT L S V D K AK S S AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 763) RFT L S V D K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 764) RFT L S V D K AK S SLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 765) RFT L S V D K AK S SLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 766) RFT L S V D K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 767) RFT L S V D K AKNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 768) RFT L S V D K AKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 769) RFT L S V D K AKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 770) RFT L S V DNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 771) RFT L S V DNAK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 772) RFT L S V DNAK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 773) RFT L S V DNAK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 774) RFT L S V DNAKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 775) RFT L SRD K A S NS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 776) RFT L SRD K A S NS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 777) RFT L SRD K A S NS AYLQLNSLRAEDTAVYYCA T  (SEQ ID NO: 778) RFT L SRD K A S NSLY MQLNSLRAEDTAVYYCA T  (SEQ ID NO: 779) RFT L SRD K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 780) RFT L SRDNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 781) RFTIS V D K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 782) RFTIS V D K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 783) RFTIS V D K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 784) RFTIS V D K AK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 785) RFTIS V D K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 786) RFTISRD K AKSS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 787) R A T L S V D K A S NS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 788) R A T L S V D K A S NS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 789) R A T L S V D K A S NS AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 790) R A T L S V D K A S NSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 791) R A T L S V D K A S NSLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 792) R A T L S V D K A S NSLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 793) R A T L S V D K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 794) R A T L S V D K AKNS A Y MQMNSLRAEDTAVYYCAT (SEQ ID NO: 795) R A T L S V D K AKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 796) R A T L S V D K AKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 797) R A T L S V DNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 798) R A T L S V DNAK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 799) R A T L S V DNAK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 800) R A T L S V DNAK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 801) R A T L S V DNAKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 802) R A T L SRD K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 803) R A T L SRD K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 804) R A T L SRD K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 805) R A T L SRD K AK S SLY M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 806) R A T L SRD K AKNS A Y M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 807) R A T L SRDNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 808) R A TIS V D K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 809) R A TIS V D K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 810) R A TIS V D K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 811) R A TIS V D K AK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 812) R A TIS V D K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 813) R A TIS V DNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 814) R A TISRD K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 815) RFT L S V D K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 816) RFT L S V D K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 817) RFT L S V D K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 818) RFT L S V D K AK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 819) RFT L S V D K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 820) RFT L S V DNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 821) RFT L SRD K ASNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 822) RFTIS V D K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 823) R A T L S V D K ASNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 824) R A T L S V D K ASNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 825) R A T L S V D K ASNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 826) R A T L S V D K ASNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 827) R A T L S V D K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 828) R A T L S V DNAKSS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 829) R A T L SRD K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 830) R A TIS V D K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 831) RFT L S V D K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 832) R A TLS V D K ASNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 833) 76E1-huVH3a VH CDR3STMITPFDY (SEQ ID NO: 32) ST L ITPFDY (SEQ ID NO: 319)76E1-huVH3a VH FR4 WGQGTLVTVSS (SEQ ID NO: 54) WGQGTL LTVSS (SEQ ID NO: 320) 76E1-huVH3b Variable RegionEVQLVESGGGLVQPGGSLRLSCAASGYSFTGYNMNWVRQAPGKGLEWVSNIDPYYDYTSYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARSTMITPFDYWGQGTLVTVSS(SEQ ID NO: 15) 76E1-huVH3b VH FR1EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 55) EVQLV QSGGGLVQPGGSLRLSCAAS (SEQ ID NO: 115) EVQLVESGGGLVQPGGS VRLSCAAS (SEQ ID NO: 116) EVQLVESGGGLVQPGGSLR I SCAAS (SEQ ID NO: 117)EVQLV Q SGGGLVQPGGS V RLSCAAS (SEQ ID NO: 118) EVQLVESGGGLVQPGGS V R ISCAAS (SEQ ID NO: 119) EVQLV Q SGGGLVQPGGSLR I SCAAS (SEQ ID NO: 120)EVQLV Q SGGGLVQPGGS V R I SCAAS (SEQ ID NO: 121) 76E1-huVH3b VH CDR1GYSFTGYNMN (SEQ ID NO: 30) GYSFTGY Q MN (SEQ ID NO: 59) GYSFTGY SMN (SEQ ID NO: 60) GYSFTGY D MN (SEQ ID NO: 61) GYSFTGY AMN (SEQ ID NO: 62) 76E1-huVH3b VH FR2 WVRQAPGKGLEWVS (SEQ ID NO: 56)WVRQAPGK S LEWVS (SEQ ID NO: 323) WVRQAPGKGLEW I S (SEQ ID NO: 122)WVRQAPGKGLEWV G  (SEQ ID NO: 123) VWRQAPGK S LEV I S (SEQ ID NO: 324)WVRQAPGK S LEWV G  (SEQ ID NO: 325) WVRQAPGKGLEW IG  (SEQ ID NO: 124)WVRQAPGK S LEW IG  (SEQ ID NO: 326) 76E1-huVH3b VH CDR2*NIDPYYDYTSYADSVKG (SEQ ID NO: 835) NI E PYYDYTSYADSVKG (SEQ ID NO: 836)NI S PYYDYTSYADSVKG (SEQ ID NO: 837) NI APYYDYTSYADSVKG (SEQ ID NO: 838) NIDPYYDYTSYADS V KG (SEQ ID NO: 839) NIE PYYDYTSYADS V KG (SEQ ID NO: 840) NI S PYYDYTSYADS VKG (SEQ ID NO: 841) NI A PYYDYTSYADS V KG (SEQ ID NO: 842)76E1-huVH3b VH FR3 RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 57) R ATISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 327) RFT LSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 328) RFTIS VDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 329) RFTISRD KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 330) RFTISRDNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 331) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 332) RFTISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 333) RFTISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 334) RFTISRDNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 335) R A T L SRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 336)R A TIS V DNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 337) R A TISRD KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 338) R A TISRDNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 339) R A TISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 340) R A TISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 341) R A TISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 342) R A TISRDNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 343) RFT L S V DNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 344)RFT L SRD K AKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 345) RFT L SRDNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 346) RFT L SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 347) RFT L SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 348) RFT L SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 349) RFT L SRDNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 350) RFTIS V D K AKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 351)RFTIS V DNAK S SLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 352) RFTIS V DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 353) RFTIS V DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 354) RFTIS V DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 355) RFTIS V DNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 356) RFTISRD K AK S SLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 357)RFTISRD K AKNS A YLQMNSLRAEDTAVYYCAR (SEQ ID NO: 358) RFTISRD K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 359) RFTISRD K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 360) RFTISRD K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 361) RFTISRDNAK S S A YLQMNSLRAEDTAVYYCAR (SEQ ID NO: 362)RFTISRDNAK S SLY M QMNSLRAEDTAVYYCAR (SEQ ID NO: 363) RFTISRDNAK S SLYLQL NSLRAEDTAVYYCAR (SEQ ID NO: 364) RFTISRDNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 365) RFTISRDNAKNS A Y M QMNSLRAEDTAVYYCAR (SEQ ID NO: 366)RFTISRDNAKNS A YLQ L NSLRAEDTAVYYCAR (SEQ ID NO: 367) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 368) RFTISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 369) RFTISRDNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 370) RFTISRDNAKNSLYLQ L NSLRAEDTAVYYCA T  (SEQ ID NO: 371)R A T L S V DNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 372) R A T L SRD KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 373) R A T L SRDNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 374) R A T L SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 375) R A T L SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 376) R A T L SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 377) R A T L SRDNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 378) R A TIS V DKAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 379)R A TIS V DNAK S SLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 380) R A TIS V DNAKNSA YLQMNSLRAEDTAVYYCAR (SEQ ID NO: 381) R A TIS V DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 382) R A TIS V DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 383) R A TIS V DNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 384) R A TISRD K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 385) R A TISRD K AKNS AYLQMNSLRAEDTAVYYCAR CSEQ ID NO: 386) R A TISRD K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 387) R A TISRD K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 388) R A TISRD K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 389) R A TISRDNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 390) R A TISRDNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 391) R A TISRDNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 392) R A TISRDNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 393) R A TISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 394) R A TISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 395) R A TISRDNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 396) R A TISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 397) R A TISRDNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 398) R A TISRDNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 399) RFT L S V D KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 400) RFT L S V DNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 401) RFT L S V DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 402) RFT L S V DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 403) RFT L S V DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 404) RFT L S V DNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 405) RFT L SRD K A SNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 406) RFT L SRDKAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 407) RFT L SRDKAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 408) RFT L SRDKAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 409) RFT L SRDKAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 410) RFT L SRDNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 411) RFT L SRDNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 412) RFT L SRDNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 413) RFT L SRDNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 414) RFT L SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 415) RFT L SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 416) RFT L SRDNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 417) RFT L SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 418) RFT L SRDNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 419) RFT L SRDNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 420) RFTIS V D K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 421) RFTIS V D K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 422) RFTIS V D K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 423) RFTIS V D K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 424) RFTIS V D K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 425) RFTIS V DNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 426) RFTIS V DNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 427) RFTIS V DNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 428) RFTIS V DNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 429) RFTIS V DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 430) RFTIS V DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 431) RFTIS V DNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 432) RFTIS V DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 433) RFTIS V DNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 434) RFTIS V DNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 435) RFTISRD K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 436) RFTISRD K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 437) RFTISRD K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 438) RFTISRD K AK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 439) RFTISRD K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 440) RFTISRD K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 441) RFTISRD K AKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 442) RFTISRD K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 443) RFTISRD K AKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 444) RFTISRD K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 445) RFTISRDNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 446) RFTISRDNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 447) RFTISRDNAK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 448) RFTISRDNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 449) RFTISRDNAK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 450) RFTISRDNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 451) RFTISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 452) RFTISRDNAKNS A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 453) RFTISRDNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 454) RFTISRDNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 455) R A T L S V D KAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 456) R A T L S V DNAK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 457) R A T L S V DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 458) R A T L S V DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 459) R A T L S V DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 460) R A T L S V DNAKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 461) R A T L SRD K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 462) R A T L SRD K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 463) R A T L SRD K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 464) R A T L SRD K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 465) R A T L SRD K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 466) R A T L SRDNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 467) R A T L SRDNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 468) R A T L SRDNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 469) R A T L SRDNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 470) R A T L SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 471) R A T L SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 472) R A T L SRDNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 473) R A T L SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 474) R A T L SRDNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 475) R A T L SRDNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 476) R A TIS V D K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 477) R A TIS V D K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 478) R A TIS V D K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 479) R A TIS V D K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 480) R A TIS V D K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 481) R A TIS V DNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 482) R A TIS V DNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 483) R A TIS V DNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 484) R A TIS V DNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 485) R A TIS V DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 486) R A TIS V DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 487) R A TIS V DNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 488) R A TIS V DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 489) R A TIS V DNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 490) R A TIS V DNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 491) R A TISRD K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 492) R A TISRD K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 493) R A TISRD K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 494) R A TISRD K AK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 495) R A TISRD K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 496) R A TISRD K AKNSAYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 497) R A TISRD K AKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 498) R A TISRD K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 499) R A TISRD K AKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 500) R A TISRD K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 501) R A TISRDNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 502) R A TISRDNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 503) R A TISRDNAK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 504) R A TISRDNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 505) R A TISRDNAK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 506) R A TISRDNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 507) R A TISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 508) R A TISRDNAKNS A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 509) R A TISRDNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 510) R A TISRDNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 511) RFT L S V D K AK SSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 512) RFT L S V D K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 513) RFT L S V D K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 514) RFT L S V D K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 515) RFT L S V D K AKNSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 516) RFT L S V DNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 517) RFT L S V DNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 518) RFT L S V DNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 519) RFT L S V DNAK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 520) RFT L S V DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 521) RFT L S V DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 522) RFT L S V DNAKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 523) RFT L S V DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 524) RFT L S V DNAKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 525) RFT L S V DNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 526) RFT L SRD K A S NS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 527) RFT L SRD K A S NSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 528) RFT L SRD K A S NSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 529) RFT L SRD K A S NSLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 530) RFT L SRD K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 531) RFT L SRD K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 532) RFT L SRD K AKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 533) RFT L SRD K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 534) RFT L SRD K AKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 535) RFT L SRD K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 536) RFT L SRDNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 537) RFT L SRDNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 538) RFT L SRDNAK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 539) RFT L SRDNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 540) RFT L SRDNAK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 541) RFT L SRDNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 542) RFT L SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 543) RFT L SRDNAKNS A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 544) RFT L SRDNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 545) RFT L SRDNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 546) RFTIS V D K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 547) RFTIS V D K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 548) RFTIS V D K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 549) RFTIS V D K AK S SLYLQMNSLRAEDTAVYYCA T (SEQ ID NO: 550) RFTIS V D K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 551) RFTIS V D K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 552) RFTIS V D K AKNS A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 553) RFTIS V D K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 554) RFTIS V D K AKNSLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 555) RFTIS V D K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 556) RFTIS V DNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 557) RFTIS V DNAK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 558) RFTIS V DNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 559) RFTIS V DNAK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 560) RFTIS V DNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 561) RFTIS V DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 562) RFTIS V DNAKNS A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 563 RFTIS V DNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 564) RFTIS V DNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 565) RFTISRD K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 566) RFTISRD K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 567) RFTISRD K AK S S A YLQMNSLRAEDTAVYYCA T (SEQ ID NO: 568) RFTISRD K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 569) RFTISRD K AK S SLY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 570) RFTISRD K AK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 571) RFTISRD K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 572) RFTISRD K AKNSAY M QMNSLRAEDTAVYYCA T (SEQ ID NO: 573) RFTISRD K AKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 574) RFTISRDKAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 575) RFTISRDNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 576) RFTISRDNAK S S A Y M QMNSLRAEDTAVYYCA T (SEQ ID NO: 577) RFTISRDNAK S S A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 578) RFTISRDNAK S SLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 579) RFTISRDNAKNS A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 580) R A T L S V D KASNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 581) R A T L S V D K AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 582) R A T L S V D K AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 583) R A T L S V D K AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 584) R A T L S V D K AKNSLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 585) R A T L S V DNAK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 586) R A T L S V DNAK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 587) R A T L S V DNAK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 588) R A T L S V DNAK S SLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 589) R A T L S V DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 590) R A T L S V DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 591) R A T L S V DNAKNS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 592) R A T L S V DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 593) R A T L S V DNAKNSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 594) R A T L S V DNAKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 595) R A T L SRD K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 596) R A T L SRD K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 597) R A T L SRD K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 598) R A T L SRD K AK S SLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 599) R A T L SRD K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 600) R A T L SRD K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 601) R A T L SRD K AKNS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 602) R A T L SRD K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 603) R A T L SRD K AKNSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 604) R A T L SRD K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 605) R A T L SRDNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 606) R A T L SRDNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 607) R A T L SRDNAK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 608) R A T L SRDNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 609) R A T L SRDNAK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 610) R A T L SRDNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 611) R A T L SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 612) R A T L SRDNAKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 613) R A T L SRDNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 614) R A T L SRDNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 615) R A TIS V D K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 616) R A TIS V D K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 617) R A TIS V D K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 618) R A TIS V D K AK S SLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 619) R A TIS V D K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 620) R A TIS V D K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 621) R A TIS V D K AKNS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 622) R A TIS V D K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 623) R A TIS V D K AKNSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 624) R A TIS V D K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 625) R A TIS V DNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 626) R A TIS V DNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 627) R A TIS V DNAK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 628) R A TIS V DNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 629) R A TIS V DNAK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 630) R A TIS V DNAK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 631) R A TIS V DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 632) R A TIS V DNAKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 633) R A TIS V DNAKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 634) R A TIS V DNAKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 635) R A TISRD K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 636) R A TISRD K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 637) R A TISRD K AK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 638) R A TISRD K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 639) R A TISRD K AK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 640) R A TISRD K AK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 641) R A TISRD K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 642) R A TISRD K AKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 643) R A TISRD K AKNS A YLQ LNSLRAEDTAVYYCAT (SEQ ID NO: 644) R A TISRD K AKNSLY M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 645) R A TISRDNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 646) R A TISRDNAK S S A Y MQMNSLRAEDTAVYYCAT (SEQ ID NO: 647) R A TISRDNAK S SAYLQ LNSLRAEDTAVYYCAT (SEQ ID NO: 648) R A TISRDNAK S SLY M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 649) R A TISRDNAKNS A Y M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 650) RFT L S V D K AK S S AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 651) RFT L S V D K AK S SLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 652) RFT L S V D K AK S SLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 653) RFT L S V D K AK S SLYLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 654) RFT L S V D K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 655) RFT L S V D K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 656) RFT L S V D K AKNS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 657) RFT L S V D K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 658) RFT L S V D K AKNSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 659) RFT L S V D K AKNSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 660) RFT L S V DNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 661) RFT L S V DNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 662) RFT L S V DNAK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 663) RFT L S V DNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 664) RFT L S V DNAK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 665) RFT L S V DNAK S SLYLQ LNSLRAEDTAVYYCAT (SEQ ID NO: 666) RFT L S V DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 667) RFT L S V DNAKNS A Y MQMNSLRAEDTAVYYCAT (SEQ ID NO: 668) RFT L S V DNAKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 669) RFT L S V DNAKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 670) RFT L SRD K A S NS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 671) RFT L SRD K A S NS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 672) RFT L SRD K A S NS A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 673) RFT L SRD K A S NSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 674) RFT L SRD K A S NSLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 675) RFT L SRD K A S NSLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 676) RFT L SRD K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 677) RFT L SRD K AKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 678) RFT L SRD K AKNS A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 679) RFT L SRD K AKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 680) RFT L SRDNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 681) RFT L SRDNAK S S A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 682) RFT L SRDNAK S S A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 683) RFT L SRDNAK S SLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 684) RFT L SRDNAKNS A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 685) RFTIS V D K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 686) RFTIS V D K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 687) RFTIS V D K AK S S A YLQMNSLRAEDTAVYYCAT  (SEQ ID NO: 688) RFTIS V D K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 689) RFTIS V D K AK S SLY M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 690) RFTIS V D K AK S SLYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 691) RFTIS V D K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 692) RFTIS V D K AKNS A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 693) RFTIS V D K AKNSAYLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 694) RFTIS V D K AKNSLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 695) RFTIS V DNAK S S A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 696) RFTIS V DNAK S SLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 697) RFTIS V DNAKNS A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 698) RFTISRD K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 699) RFTISRD K AK S S A Y M QMNSLRAEDTAVYYCAT  (SEQ ID NO: 700) RFTISRD K AK S S A YLQ L NSLRAEDTAVYYCA T (SEQ ID NO: 701) RFTISRD K AK S SLY M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 702) RFTISRD K AKNS A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 703) RFTISRDNAK S S A Y M Q L NSLRAEDTAVYYCA T (SEQ ID NO: 704) R A T L S V D K A S NS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 705) R A T L S V D K A S NSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 706) R A T L S V D K A S NSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 707) R A T L S V D K A SNSLYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 708) R A T L S V D K AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 709) R A T L S V D K AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 710) R A T L S V D K AKNS AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 711) R A T L S V D K AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 712) R A T L S V D K AKNSLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 713) R A T L S V D K AKNSLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 714) R A T L S V DNAK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 715) R A T L S V DNAK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 716) R A T L S V DNAK S S AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 717) R A T L S V DNAK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 718) R A T L S V DNAK S SLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 719) R A T L S V DNAK S SLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 720) R A T L S V DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 721) R A T L S V DNAKNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 722) R A T L S V DNAKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 723) R A T L S V DNAKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 724) R A T L SRD K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 725) R A T L SRD K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 726) R A T L SRD K AK S S AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 727) R A T L SRD K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 728) R A T L SRD K AK S SLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 729) R A T L SRD K AK S SLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 730) R A T L SRD K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 731) R A T L SRD K AKNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 732) R A T L SRD K AKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 733) R A T L SRD K AKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 734) R A T L SRDNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 735) R A T L SRDNAK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 736) R A T L SRDNAK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 737) R A T L SRDNAK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 738) R A T L SRDNAKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 739) R A TIS V D K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 740) R A TIS V D K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 741) R A TIS V D K AK S S AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 742) R A TIS V D K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 743) R A TIS V D K AK S SLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 744) R A TIS V D K AK S SLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 745) R A TIS V D K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 746) R A TIS V D K AKNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 747) R A TIS V D K AKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 748) R A TIS V D K AKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 749) RA TIS V DNAK S S A YMQ LNSLRAEDTAVYYCAR (SEQ ID NO: 750) R A TIS V DNAK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 751) R A TIS V DNAK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 752) R A TIS V DNAK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 753) R A TIS V DNAKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 754) R A TISRD K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 755) R A TISRD K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 756) R A TISRD K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 757) R A TISRD K AK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 758) R A TISRD K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 759) R A TISRDNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 760) RFT L S V D K AK S S A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 761) RFT L S V D K AK S S A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 762) RFT L S V D K AK S S AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 763) RFT L S V D K AK S SLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 764) RFT L S V D K AK S SLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 765) RFT L S V D K AK S SLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 766) RFT L S V D K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 767) RFT L S V D K AKNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 768) RFT L S V D K AKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 769) RFT L S V D K AKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 770) RFT L S V DNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 771) RFT L S V DNAK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 772) RFT L S V DNAK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 773) RFT L S V DNAK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 774) RFT L S V DNAKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 775) RFT L SRD K A S NS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 776) RFT L SRD K A S NS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 777) RFT L SRD K A S NS AYLQLNSLRAEDTAVYYCA T  (SEQ ID NO: 778) RFT L SRD K A S NSLY MQLNSLRAEDTAVYYCA T  (SEQ ID NO: 779) RFT L SRD K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 780) RFT L SRDNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 781) RFTIS V D K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 782) RFTIS V D K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 783) RFTIS V D K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 784) RFTIS V D K AK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 785) RFTIS V D K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 786) RFTISRD K AKSS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 787) R A T L S V D K A S NS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 788) R A T L S V D K A S NS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 789) R A T L S V D K A S NS AYLQMNSLRAEDTAVYYCA T  (SEQ ID NO: 790) R A T L S V D K A S NSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 791) R A T L S V D K A S NSLY MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 792) R A T L S V D K A S NSLYLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 793) R A T L S V D K AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 794) R A T L S V D K AKNS A Y MQMNSLRAEDTAVYYCAT (SEQ ID NO: 795) R A T L S V D K AKNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 796) R A T L S V D K AKNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 797) R A T L S V DNAK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 798) R A T L S V DNAK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 799) R A T L S V DNAK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 800) R A T L S V DNAK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 801) R A T L S V DNAKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 802) R A T L SRD K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 803) R A T L SRD K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 804) R A T L SRD K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 805) R A T L SRD K AK S SLY M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 806) R A T L SRD K AKNS A Y M Q LNSLRAEDTAVYYCAT (SEQ ID NO: 807) R A T L SRDNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 808) R A TIS V D K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 809) R A TIS V D K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 810) R A TIS V D K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 811) R A TIS V D K AK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 812) R A TIS V D K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 813) R A TIS V DNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 814) R A TISRD K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 815) RFT L S V D K AK S S A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 816) RFT L S V D K AK S S A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 817) RFT L S V D K AK S S A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 818) RFT L S V D K AK S SLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 819) RFT L S V D K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 820) RFT L S V DNAK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 821) RFT L SRD K ASNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 822) RFTIS V D K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 823) R A T L S V D K ASNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 824) R A T L S V D K ASNS A Y MQMNSLRAEDTAVYYCA T  (SEQ ID NO: 825) R A T L S V D K ASNS A YLQ LNSLRAEDTAVYYCA T  (SEQ ID NO: 826) R A T L S V D K ASNSLY M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 827) R A T L S V D K AKNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 828) R A T L S V DNAKSS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 829) R A T L SRD K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 830) R A TIS V D K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 831) RFT L S V D K AK S S A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 832) R A TLS V D K ASNS A Y M Q LNSLRAEDTAVYYCA T  (SEQ ID NO: 833) 76E1-huVH3b VH CDR3STMITPFDY (SEQ ID NO: 32) ST L ITPFDY (SEQ ID NO: 319)76E1-huVH3b VH FR4 WGQGTLVTVSS (SEQ ID NO: 54) WGQGTL LTVSS (SEQ ID NO: 320) 76E1 HUMANIZED ANTIBODY SEQUENCE: LIGHT CHAIN76E1-huVK2 Variable RegionDIVMTQSPLSLPVTPGEPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFILKISRVEAEDVGVYYCFQGSHVPWIFGQGTKLEIK (SEQ ID NO: 24)76E1-huVK2 VL FR1 DIVMTQSPLSLPVTPGEPASISC (SEQ ID NO: 75) D VVMTQSPLSLPVTPGEPASISC (SEQ ID NO: 252) 76E1-huVK2 VL CDR1RSSQSIVHSNGNTYLE (SEQ ID NO: 45) RSSQSIVHS Q GNTYLE (SEQ ID NO: 253)RSSQSIVHS S GNTYLE (SEQ ID NO: 254) RSSQSIVHS A GNTYLE (SEQ ID NO: 255)RSSQSIVHSNG Q TYLE (SEQ ID NO: 256) RSSQSIVHSNG S TYLE (SEQ ID NO: 257)RSSQSIVHSNG A TYLE (SEQ ID NO: 258) RSSQSIVHSNG D TYLE (SEQ ID NO: 259)RSSQSIVHS Q G Q TYLE (SEQ ID NO: 260) RSSQSIVHS Q G STYLE (SEQ ID NO: 261) RSSQSIVHS Q G A TYLE (SEQ ID NO: 262) RSSQSIVHS QG D TYLE (SEQ ID NO: 263) RSSQSIVHS S G Q TYLE (SEQ ID NO: 264)RSSQSIVHS S G S TYLE (SEQ ID NO: 265) RSSQSIVHS S G ATYLE (SEQ ID NO: 266) RSSQSIVHS S G D TYLE (SEQ ID NO: 267) RSSQSIVHS AG Q TYLE (SEQ ID NO: 268) RSSQSIVHS A G S TYLE (SEQ ID NO: 269)RSSQSIVHS A G A TYLE (SEQ ID NO: 270) RSSQSIVHS A G DTYLE (SEQ ID NO: 271) 76E1-huVK2 VL FR2 WYLQKPGQSPQLLIY (SEQ ID NO: 76)76E1-huVK2 VL CDR2 KVSNRFS (SEQ ID NO: 40) KVS Q RFS (SEQ ID NO: 843)KVS S RFS (SEQ ID NO: 844) KVS D RFS (SEQ ID NO: 845) KVS ARFS (SEQ ID NO: 846) 76E1-huVK2 VL FR3GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYC (SEQ ID NO: 77)GVPDRFSGSGSGTDFTLKISRVEAED L GVYYC (SEQ ID NO: 276) 76E1-huVK2 VL CDR3FQGSHVPWT (SEQ ID NO: 41) 76E1-huVK2 VL FR4 FGQGTKLEIK (SEQ ID NO: 78)76E1-huVK1 Variable RegionDIQ MTQSPSSLSASVGDRVTITCRSSQSIVHSNGNTYLEWYQQKPGKAPKLLIYKVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQGSHVPWTFGQGTKLEIK (SEQ ID NO: 25)76E1-huVK1 VL FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 79) D VQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 277) DIQMTQSPSSLS VSVGDRVTITC (SEQ ID NO: 278) DIQMTQSPSSLSASVGDR A TITC (SEQ ID NO: 279) DV QMTQSPSSLS V SVGDRVTITC (SEQ ID NO: 280) D V QMTQSPSSLSASVGDR ATITC (SEQ ID NO: 281) DIQMTQSPSSLS V SVGDR A TITC (SEQ ID NO: 282) D VQMTQSPSSLS V SVGDR A TITC (SEQ ID NO: 283) 76E1-huVK1 VL CDR1RSSQSIVHSNGNTYLE (SEQ ID NO: 45) RSSQSIVHS Q GNTYLE (SEQ ID NO: 253)RSSQSIVHS S GNTYLE (SEQ ID NO: 254) RSSQSIVHS A GNTYLE (SEQ ID NO: 255)RSSQSIVHSNG Q TYLE (SEQ ID NO: 256) RSSQSIVHSNG S TYLE (SEQ ID NO: 257)RSSQSIVHSNG A TYLE (SEQ ID NO: 258) RSSQSIVHSNG D TYLE (SEQ ID NO: 259)RSSQSIVHS Q G Q TYLE (SEQ ID NO: 260) RSSQSIVHS Q G STYLE (SEQ ID NO: 261) RSSQSIVHS Q G A TYLE (SEQ ID NO: 262) RSSQSIVHS QG D TYLE (SEQ ID NO: 263) RSSQSIVHS S G Q TYLE (SEQ ID NO: 264)RSSQSIVHS S G S TYLE (SEQ ID NO: 265) RSSQSIVHS S G ATYLE (SEQ ID NO: 266) RSSQSIVHS S G D TYLE (SEQ ID NO: 267) RSSQSIVHS AG Q TYLE (SEQ ID NO: 268) RSSQSIVHS A G S TYLE (SEQ ID NO: 269)RSSQSIVHS A G A TYLE (SEQ ID NO: 270) RSSQSIVHS A G DTYLE (SEQ ID NO: 271) 76E1-huVK1 VL FR2 WYQQKPGKAPKLLIY (SEQ ID NO: 80)WYQQKPGK S PKLLIY (SEQ ID NO: 284) 76E1-huVK1 VL CDR2KVSNRFS (SEQ ID NO: 40) KVS Q RFS (SEQ ID NO: 843) KVS SRFS (SEQ ID NO: 844) KVS D RFS (SEQ ID NO: 845) KVS ARFS (SEQ ID NO: 846) 76E1-huVK1 VL FR3GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 81) GVPSRFSGSGSGTDFTLTISS VQPEDFATYYC (SEQ ID NO: 285) GVPSRFSGSGSGTDFTLTISSLQPED LATYYC (SEQ ID NO: 286) GVPSRFSGSGSGTDFTLTISSLQPEDF GTYYC (SEQ ID NO: 287) GVPSRFSGSGSGTDFTLTISS V QPED LATYYC (SEQ ID NO: 288) GVPSRFSGSGSGTDFTLTISS V QPEDF GTYYC (SEQ ID NO: 289) GVPSRFSGSGSGTDFTLTISSLQPED LGTYYC (SEQ ID NO: 290) GVPSRFSGSGSGTDFTLTISS V QPED LGTYYC (SEQ ID NO: 291) 76E1-huVK1 VL CDR3 FQGSHVPWT (SEQ ID NO: 41)76E1-huVK1 VL FR4 FGQGTKLEIK (SEQ ID NO: 78) *Amino acid positionnumbering as in Kabat.

TABLE 7 Amino Acid Sequences derived from Murine 141A Antibody.141A HUMANIZED ANTIBODY SEQUENCE HEAVY CHAIN141-A huVH1a Variable RegionQVQLVQSGAEVKKPGASVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYNEKFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREEVYDGYPWFGYWGQGTLVTVSS (SEQ ID NO: 16) 141A-huVH1a VH FR1QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 51) QVQLVQSGAEV MKPGASVKVSCKAS (SEQ ID NO: 39) QVQLVQSGAEVKKPGASVK ISCKAS SEQ ID NO: 105) QVQLVQSGAEV M KPGASVK I SCKAS (SEQ ID NO: 58)141A-huVH1a VH CDR1 GYTFSRYWIE (SEQ ID NO: 33) 141A-huVH1a VH FR2WVRQAPGQGLEWMG (SEQ ID NO: 52) WVRQAPGQGLEW I G (SEQ ID NO: 106)141A-huVH1a VH CDR2 EILPGSGSTNYNEKFKG (SEQ ID NO: 34) EILPGSGST QYNEKFKG (SEQ ID NO: 847) EILPGSGST S YNEKFKG (SEQ ID NO: 848) EILPGSGSTD YNEKFKG (SEQ ID NO: 849) EILPGSGST A YNEKFKG (SEQ ID NO: 850)EILPGSGSTNY Q EKFKG (SEQ ID NO: 851) EILPGSGSTNY SEKFKG (SEQ ID NO: 852) EILPGSGSTNY D EKFKG (SEQ ID NO: 853) EILPGSGSTNYA EKFKG (SEQ ID NO: 854) EILPGSGST Q Y Q EKFKG (SEQ ID NO: 855)EILPGSGST S Y S EKFKG (SEQ ID NO: 856) EILPGSGST D Y DEKFKG (SEQ ID NO: 857) EILPGSGST A Y A EKFKG (SEQ ID NO: 858)141A-huVH1a VH FR3 RVTMTIDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 53) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 107) RVT FTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 108) RVTMT ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 109) RVTMTTDT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 859) RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAG  (SEQ ID NO: 860) R A T FTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 110) R A TMT ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 112) R A TMTTDT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 861) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 862) RVT FTADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 111) RVT F TTDT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 863) RVT FTTDTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 864) RVTMT A DT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 865) RVTMT ADTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 866) RVTMTTDT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 867) R A T F T ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 113) R A T F TTDT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 868) R A T FTTDTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 869) R A TMT A DT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 870) R A TMT ADTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 871) R A TMTTDT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 872) RVT F T A DT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 873) RVT F T ADTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 874) RVT F TTDT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 875) RVTMT A DT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 876) R A T F T A DT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 877) R A T F T ADTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 878) R A T F TTDT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 879) R A TMT A DT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 880) RVT F T A DT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 881) R A T F T A DT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 882) 141A-huVH1a VH CDR3EEVYDGYPWFGY (SEQ ID NO: 35) EEVY E GYPWFGY (SEQ ID NO: 883) EEVY SGYPWFGY (SEQ ID NO: 884) EEVY A GYPWFGY (SEQ ID NO: 885)141A-huVH1a VH FR4 WGQGTLVTVSS (SEQ ID NO: 54)141A-huVH1b Variable RegionQVQLVQSGAEVKKPGASVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQKLQGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCAREEVYDGYPWFGYWGQGTLVTVSS (SEQ ID NO: 17) 141A-huVH1b VH FR1QVQLVQSGAEVKKPGASVKVSCKAS (SEQ ID NO: 51) QVQLVQSGAEV MKPGASVKVSCKAS (SEQ ID NO: 39) QVQLVQSGAEVKKPGASVK ISCKAS (SEQ ID NO: 105) QVQLVQSGAEV M KPGASVK I SCKAS (SEQ ID NO: 58)141A-huVH1b VH CORI GYTFSRYWIE (SEQ ID NO: 33) 141A-huVH1b VH FR2WVRQAPGQGLEWMG (SEQ ID NO: 52) WVRQAPGQGLEWIG (SEQ ID NO: 106)141A-huVH1b VH CDR2* EILPGSGSTNYAQKLQG (SEQ ID NO: 49) EILPGSGST QYAQKLQG (SEQ ID NO: 886) EILPGSGST S YAQKLQG (SEQ ID NO: 887) EILPGSGSTD YAQKLQG (SEQ ID NO: 888) EILPGSGST A YAQKLQG (SEQ ID NO: 889)EILPGSGSTNYAQK F QG (SEQ ID NO: 890) EILPGSGST Q YAQK FQG (SEQ ID NO: 891) EILPGSGST S YAQK F QG (SEQ ID NO: 892) EILPGSGST DYAQK F QG (SEQ ID NO: 893) EILPGSGST A YAQK F QG (SEQ ID NO: 894)141A-huVH1b VH FR3 RVTMTIDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 53) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 107) RVT FTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 108) RVTMT ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 109) RVTMTTDT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 859) RVTMTTDTSTSTAYMELRSLRSDDTAVYYCAG  (SEQ ID NO: 860) R A T FTTDTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 110) R A TMT ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 112) R A TMTTDT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 861) R ATMTTDTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 862) RVT FTADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 111) RVT F TTDT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 863) RVT FTTDTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 864) RVTMT A DT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 865) RVTMT ADTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 866) RVTMTTDT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 867) R A T F T ADTSTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 113) R A T F TTDT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 868) R A T FTTDTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 869) R A TMT A DT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 870) R A TMT ADTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 871) R A TMTTDT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 872) RVT F T A DT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 873) RVT F T ADTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 874) RVT F TTDT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 875) RVTMT A DT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 876) R A T F T A DT NTSTAYMELRSLRSDDTAVYYCAR (SEQ ID NO: 877) R A T F T ADTSTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 878) R A T F TTDT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 879) R A TMT A DT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 880) RVT F T A DT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 881) R A T F T A DT NTSTAYMELRSLRSDDTAVYYCA G  (SEQ ID NO: 882) 141A-huVH1b VH CDR3EEVYDGYPWFGY (SEQ ID NO: 35) 141A-huVH1b VH FR4WGQGTLVTVSS (SEQ ID NO: 54) 141A-huVH3a Variable RegionEVQLVESGGGLVQPGGSLRLSCAASGYTFSRYWIEWVRQAPGKGLEWVSEILPGSGSTNYNEKFKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREEVYDGYPWFGYWGQGTLVTVSS (SEQ ID NO: 18) 141A-huVH3a VH FR1EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 55) EVQLV QSGGGLVQPGGSLRLSCAAS (SEQ ID NO: 115) EVQLVESGGGLVQPGGS VRLSCAAS (SEQ ID NO: 116) EVQLVESGGGLVQPGGSLR I SCAAS (SEQ ID NO: 117)EVQLV Q SGGGLVQPGGS V RLSCAAS (SEQ ID NO: 118) EVQLVESGGGLVQPGGS V R ISCAAS (SEQ ID NO: 119) EVQLV Q SGGGLVQPGGSLR I SCAAS (SEQ ID NO: 120)EVQLV Q SGGGLVQPGGS V R I SCAAS (SEQ ID NO: 121) EVQLVESGGGL MQPGGSLRLSCAAS (SEQ ID NO: 895) EVQLV Q SGGGL MQPGGSLRLSCAAS (SEQ ID NO: 896) EVQLVESGGGL M QPGGS VRLSCAAS (SEQ ID NO: 897) EVQLVESGGGL M QPGGSLR I SCAAS (SEQ ID NO: 898)EVQLV Q SGGGL M QPGGS V RLSCAAS (SEQ ID NO: 899) EVQLV Q SGGGL M QPGGSLRI SCAAS (SEQ ID NO: 900) EVQLVESGGGL M QPGGS V R ISCAAS (SEQ ID NO: 901) EVQLV Q SGGGL M QPGGS V R ISCAAS (SEQ ID NO: 902) 141A-huVH3a VH CDR1 GYTFSRYWIE (SEQ ID NO: 33)141A-huVH3a VH FR2 WVRQAPGKGLEWVS (SEQ ID NO: 56) WVRQAPGKGLEW IS (SEQ ID NO: 122) WNRQAPGKGLEWV G  (SEQ ID NO: 123) WVRQAPGKGLEW IG (SEQ ID NO: 124) 141A-huVH3a VH CDR2 EILPGSGSTNYNEKFKG (SEQ ID NO: 34)EILPGSGST Q YNEKFKG (SEQ ID NO: 847) EILPGSGST SYNEKFKG (SEQ ID NO: 848) EILPGSGST D YNEKFKG (SEQ ID NO: 849) EILPGSGSTA YNEKFKG (SEQ ID NO: 850) EILPGSGSTNY Q EKFKG (SEQ ID NO: 851)EILPGSGSTNY S EKFKG (SEQ ID NO: 852) EILPGSGSTNY DEKFKG (SEQ ID NO: 853) EILPGSGSTNY A EKFKG (SEQ ID NO: 854) EILPGSGST QY Q EKFKG (SEQ ID NO: 855) EILPGSGST S Y S EKFKG (SEQ ID NO: 856)EILPGSGST D Y D EKFKG (SEQ ID NO: 857) EILPGSGST A Y AEKFKG (SEQ ID NO: 858) 141A-huVH3a VH FR3RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 57) R ATISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 125) RFT FSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 126) RFTIS ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 127) RFTISRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 128) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 129) RFTISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 130) RFTISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 131) R A T FSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 132) R A TIS ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 133) R A TISRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 134) R A TISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 135) R A TISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 136) R A TISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 137) RFT FSADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 138) RFT F SRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 139) RFT F SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 140) RFT F SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 141) RFT F SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 142) RFTIS A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 143) RFTIS A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 144) RFTIS A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 145) RFTIS A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 146) RFTISRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 147) RFTISRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 148) RFTISRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 149) RFTISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 150) RFTISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 151) RFTISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 152) R A T F S ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 153) R A T F SRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 154) R A T F SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 155) R A T F SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 156) R A T F SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 157) R A TIS A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 158) R A TIS A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 159) R A TIS A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 160) R A TIS A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 161) R A TISRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 162) R A TISRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 163) R A TISRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 164) R A TISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 165) R A TISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 166) R A TISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 167) RFT F S A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 168) RFT F S A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 169) RFT F S A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 170) RFT F S A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 171) RFT F SRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 172) RFT F SRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 173) RFT F SRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 174) RFT F SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 175) RFT F SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 176) RFT F SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 177) RFTIS A D T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 178) RFTIS A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 179) RFTIS A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 180) RFTIS A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 181) RFTIS A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 182) RFTIS A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 183) RFTISRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 184) RFTISRD T AKNS A Y LQLNSLRAEDTAVYYCAR (SEQ ID NO: 185) RFTISRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 186) RFTISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 187) R A T F S A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 188) R A T F S A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 189) R A T F S A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 190) R A T F S A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 191) R A T F SRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 192) R A T F SRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 193) R A T F SRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 194) R A T F SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 195) R A T F SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 196) R A T F SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 197) R A TIS A D T AKN ALYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 198) R A TIS A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 199) R A TIS A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 200) R A TIS A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 201) R A TIS A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 202) R A TIS A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 203) R A TISRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 204) R A TISRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 205) R A TISRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 206) R A TISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 207) RFT F S A D T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 208) RFT F S A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 209) RFT F S A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 210) RFT F S A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 211) RFT F S A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 212) RFT F S A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 213) RFT F SRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 214) RFT F SRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 215) RFT F SRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 216) RFT F SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 217) RFTISAD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 218) RFTISAD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 219) RFTISAD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 220) RFTISADNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 221) RFTISRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 222) R A T F SAD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 223) R A T F SAD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 224) R A T F SAD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 225) R A T F SADNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 226) R A T F SADNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 227) R A T F SADNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 228) R A T F SRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 229) R A T F SRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 230) R A T F SRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 231) R A T F SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 232) R A TISAD T AKN A LY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 233) R A TISAD T AKN A LYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 234) R A TISAD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 235) R A TISADNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 236) R A TISRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 237) RFT F SAD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 238) RFT F SAD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 239 RFT F SAD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 240) RFT F SADNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 241) RFT F SRDTAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 242) RFTIS A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 243) R A T F S A D T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 244) R A T F S A D T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 245) R A T F S A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 246) R A T F S A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 247) R A T F SRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 248) R A TIS A D T AKN A LY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 249) RFT F S A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 250) R A T F S A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 251) RFTISRDNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 903) R A TISRDNAKNSLYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 904)RFT F SRDNAKNSLYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 905) RFTIS ADNAKNSLYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 906) RFTISRD TAKNSLYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 907) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 908) RFTISRDNAKNSLY M QMNSLRAEDTAVYYCAG  (SEQ ID NO: 909) RFTISRDNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 910) R A T F SRDNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 911) R A TIS A DNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 912) R A TISRD T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 913) R A TISRDNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 914) R A TISRDNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 915) R A TISRDNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 916) RFT F S A DNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 917) RFT F SRD T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 918) RFT F SRDNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 919) RFT F SRDNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 920) RFT F SRDNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 921) RFTIS A D T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 922) RFTIS A DNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 923) RFTIS A DNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 924) RFTIS A DNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 925) RFTISRD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 926) RFTISRD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 927) RFTISRD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 928) RFTISRDNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 929) RFTISRDNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 930) RFTISRDNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 931) R A T F SADNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 932) R A T F SRD T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 933) R A T F SRDNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 934) R A T F SRDNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 935) R A T F SRDNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 936) R A TIS A D T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 937) R A TIS A DNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 938) R A TIS A DNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 939) R A TIS A DNAKNSLYLQLNSLRAEDTAVYYCA G (SEQ ID NO: 940) R A TISRD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 941) R A TISRD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 942) R A TISRD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 943) R A TISRDNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 944) R A TISRDNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 945) R A TISRDNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 946) RFT F S A D T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 947) RFT F S A DNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 948) RFT F S A DNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 949) RFT F S A DNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 950) RFT F SRD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 951) RFT F SRD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 952) RFT F SRD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 953) RFT F SRDNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 954) RFT F SRDNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 955) RFT F SRDNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 956) RFTIS A D T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 957) RFTIS A D T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 958) RFTIS A D T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 959) RFTIS A DNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 960) RFTIS A DNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 961) RFTIS A DNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 962) RFTISRD T AKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 963) RFTISRD T AKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 964) RFTISRD T AKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 965) RFTISRDNAKNS A Y M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 966) R A T F S A D T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 967) R A T F S A DNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 968) R A T F S A DNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 969) R A T F S A DNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 970) R A T F SRD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 971) R A T F SRD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 972) R A T F SRD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 973) R A T F SRDNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 974) R A T F SRDNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 975) R A T F SRDNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 976) R A TISAD T AKN A LYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 977) R A TISAD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 978) R A TISAD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 979) R A TISADNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 980) R A TISADNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 981) R A TISADNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 982) R A TISRD T AKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 983) R A TISRD T AKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 984) R A TISRD T AKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 985) R A TISRDNAKNS A Y M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 986) RFT F SAD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 987) RFT F SAD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 988) RFT F SAD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 989) RFT F SADNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 990) RFT F SADNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 991) RFT F SADNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 992) RFT F SRDTAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 993) RFT F SRD T AKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 994) RFT F SRD T AKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 995) RFT F SRDNAKNS A Y M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 996) RFTISAD T AKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 997) RFTISAD T AKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 998) RFTISADTAKNSLY M Q L NSLRAEDTAVYYCAG (SEQ ID NO: 999)RFTIS A DNAKNS A Y M Q L NSLRAEDTAVYYCA G  (SEQ ID NO: 1000) RFTISRD TAKNS A Y M Q L NSLRAEDTAVYYCA G  (SEQ ID NO: 1001) R A T F S A D T AKNSA YLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1002) R A T F S A D T AKNSLY MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1003) R A T F S A D T AKNSLYLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1004) R A T F S A DNAKNS A Y MQMNSLRAEDTAVYYCA G  CSEQ ID NO: 1005) R A T F S A DNAKNS A YLQ LNSLRAEDTAVYYCA G  CSEQ ID NO: 1006) R A T F S A DNAKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1007) R A T F SRD T AKNS A Y MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1008) R A T F SRD T AKNS A YLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1009) R A T F SRD T AKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1010) R A T F SRDNAKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1011) R A TIS A D T AKNALY MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1012) R A TIS A D T AKN A LYLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1013) R A TIS A D T AKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1014) R A TIS A DNAKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1015) R A TISRD T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1016) RFT F S A D T AKNS A Y MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1017) RFT F S A D T AKNS A YLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1018) RFT F S A D T AKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1019) RFT F S A DNAKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1020) RFT F SRD T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1021) RFTIS A D T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1022) R A T F S A D T AKNS A Y MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1023) R A T F S A D T AKNS A YLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1024) R A T F S A D T AKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1025) R A T F S A DNAKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1026) R A T F SRD T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1027) R A TIS A D T AKNALY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1028) RFT F S A D T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1029) R A T F S A D T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1030) 141A-huVH3a VH CDR3EEVYDGYPWFGY (SEQ ID NO: 35) EEVY E GYPWFGY (SEQ ID NO: 883) EEVY SGYPWFGY (SEQ ID NO: 884) EEVY A GYPWFGY (SEQ ID NO: 885)141A-huVH3a VH FR4 WGQGTLVTVSS (SEQ ID NO: 54)141A-huVH3b Variable RegionEVQLVESGGGLVQPGGSLRLSCAASGYTFSRYWIEWVRQAPGKGLEWVSEILPGSGSTNYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREEVYDGYPWFGYWGQGTLVTVSS (SEQ ID NO: 19) 141A-huVH3b VH FR1EVQLVESGGGLVQPGGSLRLSCAAS (SEQ ID NO: 55) EVQLV QSGGGLVQPGGSLRLSCAAS (SEQ ID NO: 115) EVQLVESGGGLVQPGGS VRLSCAAS (SEQ ID NO: 116) EVQLVESGGGLVQPGGSLR I SCAAS (SEQ ID NO: 117)EVQLV Q SGGGLVQPGGS V RLSCAAS (SEQ ID NO: 118) EVQLVESGGGLVQPGGS V R ISCAAS (SEQ ID NO: 119) EVQLV Q SGGGLVQPGGSLR I SCAAS (SEQ ID NO: 120)EVQLV Q SGGGLVQPGGS V R I SCAAS (SEQ ID NO: 121) EVQLVESGGGL MQPGGSLRLSCAAS (SEQ ID NO: 895) EVQLV Q SGGGL MQPGGSLRLSCAAS (SEQ ID NO: 896) EVQLVESGGGL M QPGGS VRLSCAAS (SEQ ID NO: 897) EVQLVESGGGL M QPGGSLR I SCAAS (SEQ ID NO: 898)EVQLV Q SGGGL M QPGGS V RLSCAAS (SEQ ID NO: 899) EVQLV Q SGGGL M QPGGSLRI SCAAS (SEQ ID NO: 900) EVQLVESGGGL M QPGGS V R ISCAAS (SEQ ID NO: 901) EVQLV Q SGGGL M QPGGS V R ISCAAS (SEQ ID NO: 902) 141A-huVH3b VH CDR1 GYTFSRYWIE (SEQ ID NO: 33)141A-huVH3b VH FR2 WVRQAPGKGLEWVS (SEQ ID NO: 56) WVRQAPGKGLEW IS (SEQ ID NO: 122) WVRQAPGKGLEWV G  (SEQ ID NO: 123) WVRQAPGKGLEW IG (SEQ ID NO: 124) 141A-huVH3b VH CDR2*EILPGSGSTNYADSVKG (SEQ ID NO: 1070) EILPGSGST QYADSVKG (SEQ ID NO: 1071) EILPGSGST S YADSVKG (SEQ ID NO: 99) EILPGSGSTD YADSVKG (SEQ ID NO: 1072) EILPGSGST A YADSVKG (SEQ ID NO: 1073)EILPGSGSTNYADS F KG (SEQ ID NO: 1074) EILPGSGST Q YADS FKG (SEQ ID NO: 1075) EILPGSGST S YADS F KG (SEQ ID NO: 1076) EILPGSGST DYADS F KG (SEQ ID NO: 1077) EILPGSGST A YADS F KG (SEQ ID NO: 1078)141A-huVH3b VH FR3 RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 57) R ATISRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 125) RFT FSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 126) RFTIS ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 127) RFTISRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 128) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 129) RFTISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 130) RFTISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 131) R A T FSRDNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 132) R A TIS ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 133) R A TISRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 134) R A TISRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 135) R A TISRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 136) R A TISRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 137) RFT FSADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 138) RFT F SRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 139) RFT F SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 140) RFT F SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 141) RFT F SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 142) RFTIS A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 143) RFTIS A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 144) RFTIS A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 145) RFTIS A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 146) RFTISRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 147) RFTISRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 148) RFTISRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 149) RFTISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 150) RFTISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 151) RFTISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 152) R A T F S ADNAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 153) R A T F SRD TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 154) R A T F SRDNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 155) R A T F SRDNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 156) R A T F SRDNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 157) R A TIS A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 158) R A TIS A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 159) R A TIS A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 160) R A TIS A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 161) R A TISRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 162) R A TISRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 163) R A TISRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 164) R A TISRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 165) R A TISRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 166) R A TISRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 167) RFT F S A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 168) RFT F S A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 169) RFT F S A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 170) RFT F S A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 171) RFT F SRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 172) RFT F SRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 173) RFT F SRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 174) RFT F SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 175) RFT F SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 176) RFT F SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 177) RFTIS A D T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 178) RFTIS A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 179) RFTIS A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 180) RFTIS A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 181) RFTIS A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 182) RFTIS A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 183) RFTISRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 184) RFTISRD T AKNS A Y LQLNSLRAEDTAVYYCAR (SEQ ID NO: 185) RFTISRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 186) RFTISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 187) R A T F S A D TAKNSLYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 188) R A T F S A DNAKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 189) R A T F S A DNAKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 190) R A T F S A DNAKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 191) R A T F SRD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 192) R A T F SRD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 193) R A T F SRD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 194) R A T F SRDNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 195) R A T F SRDNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 196) R A T F SRDNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 197) R A TIS A D T AKN ALYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 198) R A TIS A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 199) R A TIS A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 200) R A TIS A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 201) R A TIS A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 202) R A TIS A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 203) R A TISRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 204) R A TISRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 205) R A TISRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 206) R A TISRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 207) RFT F S A D T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 208) RFT F S A D T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 209) RFT F S A D T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 210) RFT F S A DNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 211) RFT F S A DNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 212) RFT F S A DNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 213) RFT F SRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 214) RFT F SRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 215) RFT F SRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 216) RFT F SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 217) RFTISAD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 218) RFTISAD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 219) RFTISAD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 220) RFTISADNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 221) RFTISRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 222) R A T F SAD T AKNS AYLQMNSLRAEDTAVYYCAR (SEQ ID NO: 223) R A T F SAD T AKNSLY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 224) R A T F SAD T AKNSLYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 225) R A T F SADNAKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 226) R A T F SADNAKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 227) R A T F SADNAKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 228) R A T F SRD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 229) R A T F SRD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 230) R A T F SRD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 231) R A T F SRDNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 232) R A TISAD T AKN A LY MQMNSLRAEDTAVYYCAR (SEQ ID NO: 233) R A TISAD T AKN A LYLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 234) R A TISAD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 235) R A TISADNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 236) R A TISRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 237) RFT F SAD T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 238) RFT F SAD T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 239 RFT F SAD T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 240) RFT F SADNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 241) RFT F SRDTAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 242) RFTIS A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 243) R A T F S A D T AKNS A Y MQMNSLRAEDTAVYYCAR (SEQ ID NO: 244) R A T F S A D T AKNS A YLQ LNSLRAEDTAVYYCAR (SEQ ID NO: 245) R A T F S A D T AKNSLY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 246) R A T F S A DNAKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 247) R A T F SRD T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 248) R A TIS A D T AKN A LY M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 249) RFT F S A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 250) R A T F S A D T AKNS A Y M Q LNSLRAEDTAVYYCAR (SEQ ID NO: 251) RFTISRDNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 903) R A TISRDNAKNSLYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 904)RFT F SRDNAKNSLYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 905) RFTIS ADNAKNSLYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 906) RFTISRD TAKNSLYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 907) RFTISRDNAKNS AYLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 908) RFTISRDNAKNSLY M QMNSLRAEDTAVYYCAG  (SEQ ID NO: 909) RFTISRDNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 910) R A T F SRDNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 911) R A TIS A DNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 912) R A TISRD T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 913) R A TISRDNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 914) R A TISRDNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 915) R A TISRDNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 916) RFT F S A DNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 917) RFT F SRD T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 918) RFT F SRDNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 919) RFT F SRDNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 920) RFT F SRDNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 921) RFTIS A D T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 922) RFTIS A DNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 923) RFTIS A DNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 924) RFTIS A DNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 925) RFTISRD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 926) RFTISRD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 927) RFTISRD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 928) RFTISRDNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 929) RFTISRDNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 930) RFTISRDNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 931) R A T F SADNAKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 932) R A T F SRD T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 933) R A T F SRDNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 934) R A T F SRDNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 935) R A T F SRDNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 936) R A TIS A D T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 937) R A TIS A DNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 938) R A TIS A DNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 939) R A TIS A DNAKNSLYLQLNSLRAEDTAVYYCA G (SEQ ID NO: 940) R A TISRD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 941) R A TISRD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 942) R A TISRD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 943) R A TISRDNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 944) R A TISRDNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 945) R A TISRDNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 946) RFT F S A D T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 947) RFT F S A DNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 948) RFT F S A DNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 949) RFT F S A DNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 950) RFT F SRD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 951) RFT F SRD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 952) RFT F SRD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 953) RFT F SRDNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 954) RFT F SRDNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 955) RFT F SRDNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 956) RFTIS A D T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 957) RFTIS A D T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 958) RFTIS A D T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 959) RFTIS A DNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 960) RFTIS A DNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 961) RFTIS A DNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 962) RFTISRD T AKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 963) RFTISRD T AKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 964) RFTISRD T AKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 965) RFTISRDNAKNS A Y M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 966) R A T F S A D T AKNSLYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 967) R A T F S A DNAKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 968) R A T F S A DNAKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 969) R A T F S A DNAKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 970) R A T F SRD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 971) R A T F SRD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 972) R A T F SRD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 973) R A T F SRDNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 974) R A T F SRDNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 975) R A T F SRDNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 976) R A TISAD T AKN A LYLQMNSLRAEDTAVYYCA G (SEQ ID NO: 977) R A TISAD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 978) R A TISAD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 979) R A TISADNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 980) R A TISADNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 981) R A TISADNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 982) R A TISRD T AKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 983) R A TISRD T AKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 984) R A TISRD T AKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 985) R A TISRDNAKNS A Y M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 986) RFT F SAD T AKNS A YLQMNSLRAEDTAVYYCA G (SEQ ID NO: 987) RFT F SAD T AKNSLY M QMNSLRAEDTAVYYCA G (SEQ ID NO: 988) RFT F SAD T AKNSLYLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 989) RFT F SADNAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 990) RFT F SADNAKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 991) RFT F SADNAKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 992) RFT F SRDTAKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 993) RFT F SRD T AKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 994) RFT F SRD T AKNSLY M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 995) RFT F SRDNAKNS A Y M Q L NSLRAEDTAVYYCA G (SEQ ID NO: 996) RFTISAD T AKNS A Y M QMNSLRAEDTAVYYCA G (SEQ ID NO: 997) RFTISAD T AKNS A YLQ L NSLRAEDTAVYYCA G (SEQ ID NO: 998) RFTISADTAKNSLY M Q L NSLRAEDTAVYYCAG (SEQ ID NO: 999)RFTIS A DNAKNS A Y M Q L NSLRAEDTAVYYCA G  (SEQ ID NO: 1000) RFTISRD TAKNS A Y M Q L NSLRAEDTAVYYCA G  (SEQ ID NO: 1001) R A T F S A D T AKNSA YLQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1002) R A T F S A D T AKNSLY MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1003) R A T F S A D T AKNSLYLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1004) R A T F S A DNAKNS A Y MQMNSLRAEDTAVYYCA G  CSEQ ID NO: 1005) R A T F S A DNAKNS A YLQ LNSLRAEDTAVYYCA G  CSEQ ID NO: 1006) R A T F S A DNAKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1007) R A T F SRD T AKNS A Y MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1008) R A T F SRD T AKNS A YLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1009) R A T F SRD T AKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1010) R A T F SRDNAKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1011) R A TIS A D T AKNALY MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1012) R A TIS A D T AKN A LYLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1013) R A TIS A D T AKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1014) R A TIS A DNAKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1015) R A TISRD T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1016) RFT F S A D T AKNS A Y MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1017) RFT F S A D T AKNS A YLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1018) RFT F S A D T AKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1019) RFT F S A DNAKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1020) RFT F SRD T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1021) RFTIS A D T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1022) R A T F S A D T AKNS A Y MQMNSLRAEDTAVYYCA G  (SEQ ID NO: 1023) R A T F S A D T AKNS A YLQ LNSLRAEDTAVYYCA G  (SEQ ID NO: 1024) R A T F S A D T AKNSLY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1025) R A T F S A DNAKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1026) R A T F SRD T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1027) R A TIS A D T AKNALY M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1028) RFT F S A D T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1029) R A T F S A D T AKNS A Y M Q LNSLRAEDTAVYYCA G  (SEQ ID NO: 1030) 141A-huVH3b VH CDR3EEVYDGYPWFGY (SEQ ID NO: 35) EEVY E GYPWFGY (SEQ ID NO: 883) EEVY SGYPWFGY (SEQ ID NO: 884) EEVY A GYPWFGY (SEQ ID NO: 885)141A-huVH3b VH FR4 WGQGTLVTVSS (SEQ ID NO: 54)141A HUMANIZED ANTIBODY SEQUENCE: LIGHT CHAIN 141A-huVK3 Variable RegionEIVLTQSPGTLSLSPGERATLSCRASSSLSYMHWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQWSSNPYTFGQGTKLEIK (SEQ ID NO: 26)141A-huVK3 VL FR1 EIVLTQSPGTLSLSPGERATLSC (SEQ ID NO: 91) EIVLTQSPGTLS ASPGERATLSC (SEQ ID NO: 1031) EIVLTQSPGTLSLSPGER V TLSC (SEQ ID NO: 1032)EIVLTQSPGILSLSPGERAT M SC (SEQ ID NO: 1033) EIVLTQSPGTLS A SPGER VTLSC (SEQ ID NO: 1034) EIVLTQSPGTLS A SPGERAT M SC (SEQ ID NO: 1035)EIVLTQSPGTLSLSPGER V T M SC (SEQ ID NO: 1036) EIVLTQSPGTLS A SPGER V T MSC (SEQ ID NO: 1037) 141A-huVK3 VL CDR1 RASSSLSYMH (SEQ ID NO: 42)141A-huVK3 VL FR2 WYQQKPGQAPRLLIY (SEQ ID NO: 92) WYQQKPGQ SPRLLIY (SEQ ID NO: 1038) WYQQKPGQAPR P LIY (SEQ ID NO: 1039)WYQQKPGQAPRL W IY (SEQ ID NO: 1040) WYQQKPGQ S PR PLIY (SEQ ID NO: 1041) WYQQKPGQ S PRL W IY (SEQ ID NO: 1042) WYQQKPGQAPRPW IY (SEQ ID NO: 1043) WYQQKPGQ S PR PW IY (SEQ ID NO: 1044)141A-huVK3 VL CDR2 ATSNLAS (SEQ ID NO: 43) ATS Q LAS (SEQ ID NO: 1045)ATS S LAS (SEQ ID NO: 1046) ATS D LAS (SEQ ID NO: 1047) ATS ALAS (SEQ ID NO: 1048) 141A-huVK3 VL FR3GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 93)GVPDRFSGSGSGTDFTLTISRLEPEDFAVYYC (SEQ ID NO: 1049) GIPDRFSGSGSGTD YTLTISRLEPEDFAVYYC (SEQ ID NO: 1050) GIPDRFSGSGSGTDFTLTISR VEPEDFAVYYC (SEQ ID NO: 1051) G V PDRFSGSGSGTD YTLTISRLEPEDFAVYYC (SEQ ID NO: 1052) G V PDRFSGSGSGTDFTLTISR VEPEDFAVYYC (SEQ ID NO: 1053) GIPDRFSGSGSGTD Y TLTISR VEPEDFAVYYC (SEQ ID NO: 1054) G V PDRFSGSGSGTD Y TLTISR VEPEDFAVYYC (SEQ ID NO: 1055) 141A-huVK3 VL CDR3QQWSSNPYT (SEQ ID NO: 44) QQWSS Q PYT (SEQ ID NO: 1056) QQWSS SPYT (SEQ ID NO: 1057) QQWSS A PYT (SEQ ID NO: 1058) 141A-huVK3 VL FR4FGQGTKLEIK (SEQ ID NO: 78) 141A-huVK1 Variable RegionDIQMTQSPSSLSASVGDRVTITCRASSSLSYMHWYQQKPGKAPKLLIYATSNLASGVPSRFSGSGSGTDFILTISSLQPEDFATYYCQQWSSNPYTFGQGTKLEIK (SEQ ID NO: 27)141A-huVK1 VL FR1 DIQMTQSPSSLSASVGDRVTITC (SEQ ID NO: 79) DIQ LTQSPSSLSASVGDRVTITC (SEQ ID NO: 1059) DIQMTQSPSSLSASVGDRVT MTC (SEQ ID NO: 1060) DIQ L TQSPSSLSASVGDRVT M TC (SEQ ID NO: 1061)141A-huVK1 VL CDR1 RASSSLSYMH (SEQ ID NO: 42) 141A-huVK1 VL FR2WYQQKPGKAPKLLIY (SEQ ID NO: 80) WYQQKPGK S PKLLIY (SEQ ID NO: 284)WYQQKPGKAPK P LIY (SEQ ID NO: 1062) WYQQKPGKAPKL W IY (SEQ ID NO: 1063)WYQQKPGK S PK P LIY (SEQ ID NO: 1064) WYQQKPGK S PKL WIY (SEQ ID NO: 1065) WYQQKPGKAPK PW IY (SEQ ID NO: 1066) WYQQKPGK S PKPW IY (SEQ ID NO: 1067) 141A-huVK1 VL CDR2 ATSNLAS (SEQ ID NO: 43) ATS QLAS (SEQ ID NO: 1045) ATS S LAS (SEQ ID NO: 1046) ATS DLAS (SEQ ID NO: 1047) ATS A LAS (SEQ ID NO: 1048) 141A-huVK1 VL FR3GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 81) GVPSRFSGSGSGTD YTLTISSLQPEDFATYYC (SEQ ID NO: 1068) GVPSRFSGSGSGTDFTLTISS VQPEDFATYYC (SEQ ID NO: 285) GVPSRFSGSGSGTD Y TLTISS VQPEDFATYYC (SEQ ID NO: 1069) 141A-huVK1 VL CDR3QQWSSNPYT (SEQ ID NO: 44) QQWSS Q PYT (SEQ ID NO: 1056) QQWSS SPYT (SEQ ID NO: 1057) QQWSS A PYT (SEQ ID NO: 1058) 141A-huVK1 VL FR4FGQGTKLEIK (SEQ ID NO: 78) *Amino acid position numbering as in Kabat.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:(a) a VH region comprising: (1) a VH CDR1 having an amino acid sequenceof SEQ ID NO:36; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO:37; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:38.In certain embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45;(2) a VL CDR2 having an amino acid sequence of SEQ ID NO:46; and (3) aVL CDR3 having an amino acid sequence of SEQ ID NO:47. In otherembodiments, the antibody further comprises a VL region having the aminoacid sequence of SEQ ID NO:6. In another embodiment, the antibodyfurther comprises a VL region having the amino acid sequence of SEQ IDNO:28. In yet other embodiments, the antibody further comprises a VLregion having the amino acid sequence of SEQ ID NO:29. In someembodiments, the antibody comprises (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO:36; (2) a VH CDR2 havingan amino acid sequence of SEQ ID NO:37; and (3) a VH CDR3 having anamino acid sequence of SEQ ID NO:38; and (b) a VL region comprising: (1)a VL CDR1 having an amino acid sequence of SEQ ID NO:45; (2) a VL CDR2having an amino acid sequence of SEQ ID NO:46; and (3) a VL CDR3 havingan amino acid sequence of SEQ ID NO:47. To the extent an antibodyprovided herein is the to “bind to a C10orf54 epitope”, it is envisionedthose antibodies also bind to a C10orf54 polypeptide, polypeptidefragment, or antigen thereof.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:(a) a VH region comprising: (1) a VH CDR1 having an amino acid sequenceof SEQ ID NO:36; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO:50; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:38.In certain embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45;(2) a VL CDR2 having an amino acid sequence of SEQ ID NO:46; and (3) aVL CDR3 having an amino acid sequence of SEQ ID NO:47. In otherembodiments, the antibody further comprises a VL region having the aminoacid sequence of SEQ ID NO:6. In another embodiment, the antibodyfurther comprises a VL region having the amino acid sequence of SEQ IDNO:28. In yet other embodiments, the antibody further comprises a VLregion having the amino acid sequence of SEQ ID NO:29. In someembodiments, the antibody comprises: (a) a VH region comprising: (1) aVH CDR1 having an amino acid sequence of SEQ ID NO:36; (2) a VH CDR2having an amino acid sequence of SEQ ID NO:50; and (3) a VH CDR3 havingan amino acid sequence of SEQ ID NO:38; and (b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45; (2) a VLCDR2 having an amino acid sequence of SEQ ID NO:46; and (3) a VL CDR3having an amino acid sequence of SEQ ID NO:47.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:(a) a VH region comprising: (1) a VH CDR1 having an amino acid sequenceof SEQ ID NO:36; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO:99; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:38.In certain embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45;(2) a VL CDR2 having an amino acid sequence of SEQ ID NO:46; and (3) aVL CDR3 having an amino acid sequence of SEQ ID NO:47. In otherembodiments, the antibody further comprises a VL region having the aminoacid sequence of SEQ ID NO:6. In another embodiment, the antibodyfurther comprises a VL region having the amino acid sequence of SEQ IDNO:28. In yet other embodiments, the antibody further comprises a VLregion having the amino acid sequence of SEQ ID NO:29. In someembodiments, the antibody comprises: (a) a VH region comprising: (1) aVH CDR1 having an amino acid sequence of SEQ ID NO:36; (2) a VH CDR2having an amino acid sequence of SEQ ID NO:99; and (3) a VH CDR3 havingan amino acid sequence of SEQ ID NO:38; and (b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45; (2) a VLCDR2 having an amino acid sequence of SEQ ID NO:46; and (3) a VL CDR3having an amino acid sequence of SEQ ID NO:47.

In another embodiment, an antibody that binds to C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope)comprises: a VL region comprising: (1) a VL CDR1 having an amino acidsequence of SEQ ID NO:45; (2) a VL CDR2 having an amino acid sequence ofSEQ ID NO:46; and (3) a VL CDR3 having an amino acid sequence of SEQ IDNO:47. In some embodiments, the antibody further comprises a VH regionhaving the amino acid sequence of SEQ ID NO:20. In another embodiment,the antibody further comprises a VH region having the amino acidsequence of SEQ ID NO:21. In other embodiments, the antibody furthercomprises a VH region having the amino acid sequence of SEQ ID NO:22. Inother embodiments, the antibody further comprises a VH region having theamino acid sequence of SEQ ID NO:23.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:(a) a VH region comprising: (1) a VH CDR1 having an amino acid sequenceof SEQ ID NO:30; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO:31; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:32.In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45;(2) a VL CDR2 having an amino acid sequence of SEQ ID NO:40; and (3) aVL CDR3 having an amino acid sequence of SEQ ID NO:41. In otherembodiments, the antibody further comprises a VL region having the aminoacid sequence of SEQ ID NO:24. In another embodiment, the antibodyfurther comprises a VL region having the amino acid sequence of SEQ IDNO:25. In one embodiment, the antibody comprises: (a) a VH regioncomprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO:30;(2) a VH CDR2 having an amino acid sequence of SEQ ID NO:31; and (3) aVH CDR3 having an amino acid sequence of SEQ ID NO:32; and (b) a VLregion comprising: (1) a VL CDR1 having an amino acid sequence of SEQ IDNO:45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO:40; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO:41.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:(a) a VH region comprising: (1) a VH CDR1 having an amino acid sequenceof SEQ ID NO:30; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO:321; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:32.In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45;(2) a VL CDR2 having an amino acid sequence of SEQ ID NO:40; and (3) aVL CDR3 having an amino acid sequence of SEQ ID NO:41. In otherembodiments, the antibody further comprises a VL region having the aminoacid sequence of SEQ ID NO:24. In another embodiment, the antibodyfurther comprises a VL region having the amino acid sequence of SEQ IDNO:25. In one embodiment, the antibody comprises: (a) a VH regioncomprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO:30;(2) a VH CDR2 having an amino acid sequence of SEQ ID NO:321; and (3) aVH CDR3 having an amino acid sequence of SEQ ID NO:32; and (b) a VLregion comprising: (1) a VL CDR1 having an amino acid sequence of SEQ IDNO:45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO:40; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO:41.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:(a) a VH region comprising: (1) a VH CDR1 having an amino acid sequenceof SEQ ID NO:30; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO:835; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:32.In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45;(2) a VL CDR2 having an amino acid sequence of SEQ ID NO:40; and (3) aVL CDR3 having an amino acid sequence of SEQ ID NO:41. In otherembodiments, the antibody further comprises a VL region having the aminoacid sequence of SEQ ID NO:24. In another embodiment, the antibodyfurther comprises a VL region having the amino acid sequence of SEQ IDNO:25. In one embodiment, the antibody comprises: (a) a VH regioncomprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO:30;(2) a VH CDR2 having an amino acid sequence of SEQ ID NO:835; and (3) aVH CDR3 having an amino acid sequence of SEQ ID NO:32; and (b) a VLregion comprising: (1) a VL CDR1 having an amino acid sequence of SEQ IDNO:45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO:40; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO:41.

In some embodiments, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:a VL region comprising: (1) a VL CDR1 having an amino acid sequence ofSEQ ID NO:45; (2) a VL CDR2 having an amino acid sequence of SEQ IDNO:40; and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO:41.In some embodiments, the antibody further comprises a VH region havingthe amino acid sequence of SEQ ID NO:12. In another embodiment, theantibody further comprises a VH region having the amino acid sequence ofSEQ ID NO:13. In other embodiments, the antibody further comprises a VHregion having the amino acid sequence of SEQ ID NO:14. In otherembodiments, the antibody further comprises a VH region having the aminoacid sequence of SEQ ID NO:15.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:(a) a VH region comprising: (1) a VH CDR1 having an amino acid sequenceof SEQ ID NO:33; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO:34; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:35.In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:42;(2) a VL CDR2 having an amino acid sequence of SEQ ID NO:43; and (3) aVL CDR3 having an amino acid sequence of SEQ ID NO:44. In otherembodiments, the antibody further comprises a VL region having the aminoacid sequence of SEQ ID NO:26. In another embodiment, the antibodyfurther comprises a VL region having the amino acid sequence of SEQ IDNO:27. In one embodiment, the antibody comprises: (a) a VH regioncomprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO:33;(2) a VH CDR2 having an amino acid sequence of SEQ ID NO:34; and (3) aVH CDR3 having an amino acid sequence of SEQ ID NO:35; and (b) a VLregion comprising: (1) a VL CDR1 having an amino acid sequence of SEQ IDNO:42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO:43; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO:44.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:(a) a VH region comprising: (1) a VH CDR1 having an amino acid sequenceof SEQ ID NO:33; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO:49; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:35.In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:42;(2) a VL CDR2 having an amino acid sequence of SEQ ID NO:43; and (3) aVL CDR3 having an amino acid sequence of SEQ ID NO:44. In otherembodiments, the antibody further comprises a VL region having the aminoacid sequence of SEQ ID NO:26. In another embodiment, the antibodyfurther comprises a VL region having the amino acid sequence of SEQ IDNO:27. In one embodiment, the antibody comprises: (a) a VH regioncomprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO:33;(2) a VH CDR2 having an amino acid sequence of SEQ ID NO:49; and (3) aVH CDR3 having an amino acid sequence of SEQ ID NO:35; and (b) a VLregion comprising: (1) a VL CDR1 having an amino acid sequence of SEQ IDNO:42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO:43; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO:44.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprises:(a) a VH region comprising: (1) a VH CDR1 having an amino acid sequenceof SEQ ID NO:33; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO:1070; and (3) a VH CDR3 having an amino acid sequence of SEQ IDNO:35. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:42;(2) a VL CDR2 having an amino acid sequence of SEQ ID NO:43; and (3) aVL CDR3 having an amino acid sequence of SEQ ID NO:44. In otherembodiments, the antibody further comprises a VL region having the aminoacid sequence of SEQ ID NO:26. In another embodiment, the antibodyfurther comprises a VL region having the amino acid sequence of SEQ IDNO:27. In one embodiment, the antibody comprises: (a) a VH regioncomprising: (1) a VH CDR1 having an amino acid sequence of SEQ ID NO:33;(2) a VH CDR2 having an amino acid sequence of SEQ ID NO:1070; and (3) aVH CDR3 having an amino acid sequence of SEQ ID NO:35; and (b) a VLregion comprising: (1) a VL CDR1 having an amino acid sequence of SEQ IDNO:42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO:43; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO:44.

As will be understood by a person skilled in the art, the boundariesbetween the CDRs and framework sequences for any of the VH regions andVL regions described herein can be determined using any one of thewell-known methods in the art, including IMGT, Kabat, Chothia, Contact,AbM or Kabat plus Chothia. Accordingly, any anti-C10orf54 antibodyhaving one or more CDR or framework sequence as described hereinincludes a CDR or framework amino acid sequence as determined usingIMGT, Kabat, Chothia, Contact, AbM or Kabat plus Chothis. For instance,exemplary CDR sequences for both VH and VL regions that can be includedin an anti-C10orf54 antibody of the invention are depicted in Tables8-10 for the [INSERT FULL NAMES OF CLONES] as disclosed in Tables 5-7.Table 8 cdr sequences based on a 175A-huVH1a variable region sequence asshown in Table 5.

TABLE 8 Antibody 175A-huVH1A CDR Sequences Exemplary* IMGT Kabat ChothiaContact AbM VH CDR VH GYTESTHWIE GYTFSTHW THWIE GYTFSTH STHWIEGYTFSTHWIE Seq. CDR1 (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ IDNO. 36) NO. 1081) NO. 1086) NO. 1087) NO. 1092) NO. 36) VH EILPGSGSTSYNILPGSPGT EILPGSGSTSYN PGSG WIGEILPGSGST EILPGSGSTS CDR2 EKFKG (SEQ IDEKFKG (SEQ ID S (SEQ ID (SEQ ID NO: 1082) (SEQ ID NO. 1088) (SEQ IDNO. 1098) NO. 37) NO. 37) NO. 1093) VH WLLYYYAMDY ARWLLYYYAMD WLLYYYAMDYLLYYYAMD ARWLLYYYAMD WLLYYYAMDY CDR3 (SEQ ID Y (SEQ ID (SEQ ID (SEQ ID(SEQ ID NO. 38) (SEQ ID NO. 38) NO. 1089) NO. 1094) NO. 38) NO. 1083)VL CDR VL RSSQSIVHSNGN QSIVHSNGNTY RSSQSIVHSNGN SQSIVHSNGNTY VHSNGNTYLEWRSSQSIVHSNGN Seq. CDR1 TYLE (SEQ ID TYLE (SEQ ID Y TYLE (SEQ IDNO. 1084) (SEQ ID NO. 1090) (SEQ ID (SEQ ID NO. 45) NO. 45) NO. 1095)NO. 45) VL KLSNRFS KLS KLSNRFS KLS LLIYKKSNRF KLSNRFS CDR2 (SEQ ID(SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID NO. 46) NO. 1085) NO. 46)NO. 1085) NO. 1096) NO. 46) VL FQGSHFPYT FQGSHFPYT FQGSHFPYT GSHFPYFQGSHFPY FQGSHFPYT CDR3 (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ IDNO. 47) NO. 47) NO. 47) NO. 1091) NO. 1097) NO. 47) VH Sequence:QVQLQQSGAELMKPGASVKISCKATGYTFSTHWIEWVKQRPGHGLEWIGEILPGSGSTSYNEKFKGKATFTADTSSNTAYMQLSSLTSEDSAVYYCARWLLYYYAMDYWGQGTSVTVSS (SEQ ID NO: 3) VL Sequence:DVLMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKLSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHFPYTFGGGTKLEIK (SEQ ID NO: 6) *Exemplary CDR sequences encompassamino acids as determined by Kabat plus Chothia

TABLE 9 Antibody 76E1-huVH1a CDR Sequences Exemplary* IMGT Kabat ChothiaContact AbM VH CDR VH GYSFTGYNMN GYSFTGYN GYNMN GYSFTGY TGYNMNGYSFTGYNMN Seq. CDR1 (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ IDNO: 30) NO: 1099) NO: 1104) NO: 1105) NO: 1110) NO: 30) VH NIDPYYDYTSYNIDPYYDYT NIDPYYDYTSYN PYYD WIGNIDPYYDYT SIDPYYDYTS CDR2 LKFKD (SEQ IDLKFKD (SEQ ID S (SEQ ID (SEQ ID NO: 1100) (SEQ ID NO: 1106) (SEQ IDNO: 1116) NO: 31) NO: 31) NO: 1111) VH STMITPFDY ATSTMITPFDY STMITPFDYTMITPFD ATSTMITPFD STMITPFDY CDR3 (SEQ ID (SEQ ID (SEQ ID (SEQ ID(SEQ ID (SEQ ID NO: 32) NO: 1101) NO: 32) NO: 1107) NO: 1112) NO: 32)VL CDR VL RSSQSIVHSNGN QSIVHSNGNTY RSSQSIVHSNGN SQSIVHSNGNTY VHSNGNTYLEWRSSQSIVHSNGN Seq. CDR1 TYLE (SEQ ID TYLE (SEQ ID Y TYLE (SEQ IDNO: 1102) (SEQ ID NO: 1108) (SEQ ID (SEQ ID NO: 45) NO: 45) NO: 1113)NO: 45) VL KVSNRFS KVS KVSNRFS KVS LLIYKVSNRF KVSNRFS CDR2 (SEQ ID(SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID NO: 40) NO: 1103) NO: 40)NO: 1103) NO: 1114) NO: 40) VL FQGSHVPWT FQGSHVPWT FQGSHVPWT GSHVPWFQGSHVPW FQGSHVPWT CDR3 (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ IDNO: 41) NO: 41) NO: 41) NO: 1109) NO: 1115) NO: 41) VH Sequence:EVQLLQSGPELEKPGASVKISCKASGYSFTGYNMNWVKQSNGKSLEWIGNIDPYYDYTSYNLKFKDKATLTVDKSSSTAYMQLKSLTSEDSAVYYCATSTMITPFDYWGQGTTLTVSS (SEQ ID NO: 1) VL Sequence:DVLMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKINRVEAEDLGVYYCFQGSHVPWTFGGGTKLEIK (SEQ ID NO: 4) *Exemplary CDR sequences encompassamino acids as determined by Kabat plus Chothia

TABLE 10 Antibody 141A-huVH1a CDR Sequences Exemplary* IMGT KabatChothia Contact AbM VH CDR VH GYTFSRYWIE GYTFSRYW RYWIE GYTFSRY SRYWIEGYTFSRYWIE Seq. CDR1 (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ IDNO: 33) NO: 1117) NO: 1122) NO: 1123) NO: 1128) NO: 33) VH EILPGSGSTNYNILPGSGST EILPGSGSTNYN PGSG WIGILPGSGNT EILPGSGSTN CDR2 EKFKG (SEQ IDEKFKG (SEQ ID N (SEQ ID (SEQ ID NO: 1118) (SEQ ID NO: 1124) (SEQ IDNO: 1134) NO: 34) NO: 34) NO: 1129) VH EEVDGYPWFG AGEEVYDGYPW EEVDGYPWFGEVYDGYPWFG AGEEVYDGYPW EEVDGYPWFG CDR3 Y FGY Y (SEQ ID FG Y (SEQ ID(SEQ ID (SEQ ID NO: 1125) (SEQ ID (SEQ ID NO: 35) NO: 1119) NO: 35)NO: 1130) NO: 35) VL CDR VL RASSSLSYMH SSLSY RSSSASSSLSYMH SSSLSY SYMHWYRASSSLSYMH Seq. CDR1 (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ IDNO: 42) NO: 1120) NO: 42) NO: 1126) NO: 1131) NO: 42) VL ATSNLAS ATSATSNLAS ATS PWIYATSNLA ATSNLAS CDR2 (SEQ ID (SEQ ID (SEQ ID (SEQ ID(SEQ ID (SEQ ID NO: 43) NO: 1121) NO: 43) NO: 1121) NO: 1132) NO: 43) VLQQWSSNPYT QQWSSNPYT QQWSSNPYT WSSNPY QQWSSNPY QQWSSNPYT CDR3 (SEQ ID(SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID NO: 44) NO: 44) NO: 44)NO: 1127) NO: 1133) NO: 44) VH Sequence:QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFKGKATFTADTSSNTAYMQLSSLTSEDSAVYYCGEEVYDGYPWFGYWGQGTLTVSA (SEQ ID NO: 2) VL Sequence:QIVLSQSPAILSASPGEKVTMTCRASSSLSYMHWYQQKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSSNPYTFGGGTKLEIK (SEQ ID NO: 5) *Exemplary CDR sequences encompass aminoacids as determined by Kabat plus Chothia

In accordance with the amino acid sequences disclosed in Tables 8-10, insome embodiments, an antibody that binds to a C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 36, 1081, 1086, 1087, 1092, 30, 1099, 1104, 1105, 1110, 33,1117, 1122, 1123 or 1128; (2) a VH CDR2 having an amino acid sequence ofSEQ ID NO: 37, 1082, 1088, 1093, 1098, 31, 1100, 1106, 1111, 1116, 34,1118, 1124, 1129 or 1134; and/or (3) a VH CDR3 having an amino acidsequence of SEQ ID NO: 38, 1083, 1089, 1094, 32, 1101, 1107, 1112, 35,1119, 1125 or 1130. In certain embodiments, an antibody that binds toC10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope) comprises a VL region comprising: (1) a VL CDR1 havingan amino acid sequence of SEQ ID NO: 45, 1084, 1090, 1095, 1102, 1108,1113, 42, 1120, 1126 or 1131; (2) a VL CDR2 having an amino acidsequence of SEQ ID NO: 46, 1085, 1096, 40, 1103, 1114, 43, 1121 and1132; and/or (3) a VL CDR3 having an amino acid sequence of SEQ ID NO:47, 1091, 1097, 41, 1109, 1115, 44, 1127 or 1133. In some embodiments,the antibody comprises: (a) a VH region comprising: (1) a VH CDR1 havingan amino acid sequence of SEQ ID NO: 36, 1081, 1086, 1087, 1092, 30,1099, 1104, 1105, 1110, 33, 1117, 1122, 1123 or 1128; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 37, 1082, 1088, 1093, 1098,31, 1100, 1106, 1111, 1116, 34, 1118, 1124, 1129 or 1134; and/or (3) aVH CDR3 having an amino acid sequence of SEQ ID NO: 38, 1083, 1089,1094, 32, 1101, 1107, 1112, 35, 1119, 1125 or 1130; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45, 1084, 1090, 1095, 1102, 1108, 1113, 42, 1120, 1126 or 1131; (2) a VLCDR2 having an amino acid sequence of SEQ ID NO: 46, 1085, 1096, 40,1103, 1114, 43, 1121 or 1132; and/or (3) a VL CDR3 having an amino acidsequence of SEQ ID NO: 47, 1091, 1097, 41, 1109, 1115, 44, 1127 or 1133.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1081; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 1082; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:1083. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1084; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1085;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In oneembodiment, the antibody comprises: (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO: 1081; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 1082; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 1083; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1084; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1085;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1086; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 37; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:38. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In oneembodiment, the antibody comprises: (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO: 1086; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 37; and (3) a VH CDR3 havingan amino acid sequence of SEQ ID NO: 38; and (b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VLCDR2 having an amino acid sequence of SEQ ID NO: 46; and (3) a VL CDR3having an amino acid sequence of SEQ ID NO: 47.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1087; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 1088; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:1089. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1090; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1085;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1091. Inone embodiment, the antibody comprises: (a) a VH region comprising: (1)a VH CDR1 having an amino acid sequence of SEQ ID NO: 1087; (2) a VHCDR2 having an amino acid sequence of SEQ ID NO: 1088; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 1089; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1090; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1085;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1091.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1092; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 1093; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:1094. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1095; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1096;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1097. Inone embodiment, the antibody comprises: (a) a VH region comprising: (1)a VH CDR1 having an amino acid sequence of SEQ ID NO: 1092; (2) a VHCDR2 having an amino acid sequence of SEQ ID NO: 1093; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 1094; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1095; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1096;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1097.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 36; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO:1098; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 38.In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47. In oneembodiment, the antibody comprises: (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO: 36; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 1098; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 38; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 46; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 47.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1099; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 1100; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:1101. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1102; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1103;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In oneembodiment, the antibody comprises: (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO: 1099; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 1100; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 1101; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1102; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1103;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1104; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 31; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:32. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In oneembodiment, the antibody comprises: (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO: 1104; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 31; and (3) a VH CDR3 havingan amino acid sequence of SEQ ID NO: 32; and (b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 45; (2) a VLCDR2 having an amino acid sequence of SEQ ID NO: 40; and (3) a VL CDR3having an amino acid sequence of SEQ ID NO: 41.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1105; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 1106; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:1107. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1108; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1103;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1109. Inone embodiment, the antibody comprises: (a) a VH region comprising: (1)a VH CDR1 having an amino acid sequence of SEQ ID NO: 1105; (2) a VHCDR2 having an amino acid sequence of SEQ ID NO: 1106; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 1107; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1108; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1103;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1109.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1110; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 1111; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:1112. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1113; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1114;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1115. Inone embodiment, the antibody comprises: (a) a VH region comprising: (1)a VH CDR1 having an amino acid sequence of SEQ ID NO: 1110; (2) a VHCDR2 having an amino acid sequence of SEQ ID NO: 1111; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 1112; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1113; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1114;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1115.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 30; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO:1116; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 32.In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41. In oneembodiment, the antibody comprises: (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO: 30; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 1116; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 32; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:45; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 40; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 41.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1117; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 1118; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:1119. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1120; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1121;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44. In oneembodiment, the antibody comprises: (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO: 1117; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 1118; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 1119; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1120; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1121;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1122; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 34; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:35. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44. In oneembodiment, the antibody comprises: (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO: 1122; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 34; and (3) a VH CDR3 havingan amino acid sequence of SEQ ID NO: 35; and (b) a VL region comprising:(1) a VL CDR1 having an amino acid sequence of SEQ ID NO: 42; (2) a VLCDR2 having an amino acid sequence of SEQ ID NO: 43; and (3) a VL CDR3having an amino acid sequence of SEQ ID NO: 44.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1123; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 1124; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:1125. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1126; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1121;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1127. Inone embodiment, the antibody comprises: (a) a VH region comprising: (1)a VH CDR1 having an amino acid sequence of SEQ ID NO: 1123; (2) a VHCDR2 having an amino acid sequence of SEQ ID NO: 1124; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 1125; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1126; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1121;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1127.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 1128; (2) a VH CDR2 having an amino acid sequence of SEQ IDNO: 1129; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO:1130. In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1131; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1132;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1133. Inone embodiment, the antibody comprises: (a) a VH region comprising: (1)a VH CDR1 having an amino acid sequence of SEQ ID NO: 1128; (2) a VHCDR2 having an amino acid sequence of SEQ ID NO: 1129; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 1130; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:1131; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 1132;and (3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 1133.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH region comprising: (1) a VH CDR1 having an amino acid sequence ofSEQ ID NO: 33; (2) a VH CDR2 having an amino acid sequence of SEQ ID NO:1134; and (3) a VH CDR3 having an amino acid sequence of SEQ ID NO: 35.In some embodiments, the antibody further comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44. In oneembodiment, the antibody comprises: (a) a VH region comprising: (1) a VHCDR1 having an amino acid sequence of SEQ ID NO: 33; (2) a VH CDR2having an amino acid sequence of SEQ ID NO: 1134; and (3) a VH CDR3having an amino acid sequence of SEQ ID NO: 35; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence of SEQ ID NO:42; (2) a VL CDR2 having an amino acid sequence of SEQ ID NO: 43; and(3) a VL CDR3 having an amino acid sequence of SEQ ID NO: 44.

In certain embodiments, a humanized anti-C10orf54 antibody that binds toC10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope) comprises one or more consensus sequences derived fromrelated antibodies as depicted in FIGS. 17A and 17B. As describedherein, a “consensus sequence” refers to amino acid sequences havingconserved amino acids common among a number of sequences and variableamino acids that vary within a given amino acid sequences. The CDRconsensus sequences provided include CDRs corresponding to CDRH1, CDRH2,CDRH3, CDRL1, CDRL2 and/or CDRL3. Consensus sequences of CDRs ofanti-C10orf54 antibodies are shown in FIGS. 17A and 17B. Accordingly, insome embodiments, a humanized anti-C10orf54 antibody comprises a VHregion comprising: (1) a VH CDR1 having an amino acid sequence ofGYTFSX_(I)X₂WIE (SEQ ID NO: 1149), wherein X₁ is a R or T and X₂ is a Yor H; (2) a VH CDR2 having an amino acid sequence of EILPGSGSTX₁YNEKFKG(SEQ ID NO: 1150), wherein X₁ is a N or S; and/or (3) a VH CDR3 havingan amino acid sequence of xxxxxxxxxX₁X₂Y (SEQ ID NO: 1151), wherein x isany amino acid residue, X₁ is a M or F, and X₂ is G or D. In certainembodiments, a humanized anti-C10orf54 antibody comprises a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence ofRSSQSIVHSNGNTYLE (SEQ ID NO: 45); (2) a VL CDR2 having an amino acidsequence of KX₁SNRFS (SEQ ID NO: 1152), wherein X₁ is a V or L; and/or(3) a VL CDR3 having an amino acid sequence of FQGSHX₁PX₂T (SEQ ID NO:1153), wherein X₁ is V or F and X₂ is a W or Y. In certain embodiments,a humanized anti-C10orf54 antibody comprises: (a) a VH regioncomprising: (1) a VH CDR1 having an amino acid sequence of GYTFSX₁X₂WIE(SEQ ID NO: 1149), wherein X₁ is a R or T and X₂ is a Y or H; (2) a VHCDR2 having an amino acid sequence of EILPGSGSTX₁YNEKFKG (SEQ ID NO:1150), wherein X₁ is a N or S; and/or (3) a VH CDR3 having an amino acidsequence of xxxxxxxxxxxX₁X₂Y (SEQ ID NO: 1151), wherein x is any aminoacid residue, X₁ is a M or F, and X₂ is G or D; and (b) a VL regioncomprising: (1) a VL CDR1 having an amino acid sequence ofRSSQSIVHSNGNTYLE (SEQ ID NO: 45); (2) a VL CDR2 having an amino acidsequence of KXISNRFS (SEQ ID NO: 1152), wherein X₁ is a V or L; and/or(3) a VL CDR3 having an amino acid sequence of FQGSHX₁PX₂T (SEQ ID NO:1153), wherein X₁ is V or F and X₂ is a W or Y.

In some embodiments, the antibodies provided herein comprise a VH regionthat comprises or consists of a VH domain. In other embodiments, theantibodies provided herein comprise a VH region that comprises orconsists of a VH chain. In some embodiments, the antibodies providedherein comprise a VL region that comprises or consists of a VL domain.In other embodiments, the antibodies provided herein comprise a VLregion that comprises or consists of a VL chain. In some embodiments,the antibodies provided herein have a combination of (i) a VH domain orVH chain; and/or (ii) a VL domain or VL chain.

In some embodiments, an antibody provided herein comprises or consistssix CDRs, for example, VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2,and/or VL CDR3 identified in Tables 5-10. In certain embodiments, anantibody provided herein can comprise less than six CDRs. In someembodiments, the antibody comprises or consists of one, two, three,four, or five CDRs selected from the group consisting of VH CDR1, VHCDR2, VH CDR3, VL CDR1, VL CDR2, and/or VL CDR3. In specificembodiments, the antibody comprises or consists of one, two, three,four, or five CDRs selected from the group consisting of VH CDR1, VHCDR2, VH CDR3, VL CDR1, VL CDR2, and/or VL CDR3 of the murine monoclonalantibody 175A, 76E1 or 141A described herein, or a humanized variantthereof, as identified in Tables 5-10. Accordingly, in some embodiments,the antibody comprises or consists of one, two, three four or five CDRsof anyone of the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and/or VLCDR3 identified in Tables 5-10.

In some embodiments, the antibodies provided herein comprise one or more(e.g. one, two or three) VH CDRs listed in Tables 5-10. In otherembodiments, the antibodies provided herein comprise one or more (e.g.,one, two or three) VL CDRs listed in Tables 5-10. In yet otherembodiments, the antibodies provided herein comprise one or more (e.g.,one, two or three) VH CDRs listed in Tables 5-10 and one or more VL CDRslisted in Tables 5-10. Accordingly, in certain embodiments, theantibodies comprise a VH CDR1 having the amino acid sequence of any oneof SEQ ID NOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104,1105, 1110, 1117, 1122, 1123 and 1128. In another embodiment, theantibodies comprise a VH CDR2 having the amino acid sequence of any oneof SEQ ID NOS: 37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321,322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093,1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 and 1134. In anotherembodiment, the antibodies comprise a VH CDR3 having the amino acidsequence of any one of SEQ ID NOS: 38, 32, 319, 35, 883-885, 1083, 1089,1094, 1101, 1107, 1112, 1119, 1125 and 1130. In certain embodiments, theantibodies comprise a VH CDR1 and/or a VH CDR2 and/or a VH CDR3independently selected from a VH CDR1, VH CDR2, VH CDR3 as depicted inany one of the VH regions depicted in Table 5-10. In certainembodiments, the antibodies comprise a VL CDR1 having the amino acidsequence of any one of SEQ ID NOS: 45, 253-271, 42, 1084, 1090, 1095,1102, 1108, 1113, 1120, 1126 and 1131. In another embodiment, theantibodies comprise a VL CDR2 having the amino acid sequence of any oneof SEQ ID NOS: 46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096,1103, 1114, 1121 and 1132. In another embodiment, the antibodiescomprise a VL CDR3 having the amino acid sequence of any one of SEQ IDNOS: 47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127 and 1133. Incertain embodiments, the antibodies comprise a VL CDR1 and/or a VL CDR2and/or a VL CDR3 independently selected from a VL CDR1, VL CDR2, VL CDR3as depicted in any one of the VL regions depicted in Tables 5-10.

Also provided herein are antibodies comprising one or more VH CDRs andone or more (e.g., one, two or three) VL CDRs listed in Tables 5-10. Inparticular, provided herein is an antibody comprising a VH CDR1 (SEQ IDNOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110,1117, 1122, 1123 or 1128) and a VL CDR1 (SEQ ID NOS:45, 253-271, 42,1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126 or 1131); a VH CDR1 (SEQID NOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105,1110, 1117, 1122, 1123 or 1128) and a VL CDR2 (SEQ ID NOS:46, 272-275,40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121 or 1132); a VHCDR1 (SEQ ID NOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104,1105, 1110, 1117, 1122, 1123 or 1128) and a VL CDR3 (SEQ ID NOS:47, 41,44, 1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR2 (SEQ IDNOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322,835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098,1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134) and a VL CDR1 (SEQ IDNOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126 or1131); a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74,83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082,1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134) anda VL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085,1096, 1103, 1114, 1121 or 1132); a VH CDR2 (SEQ ID NOS:37, 101-104, 50,114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49,886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116,1118, 1124, 1129 or 1134) and a VL CDR3 (SEQ ID NOS:47, 41, 44,1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR3 (SEQ IDNOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119,1125 or 1130) and a VL CDR1 (SEQ ID NOS:45, 253-271, 42, 1084, 1090,1095, 1102, 1108, 1113, 1120, 1126 or 1131); a VH CDR3 (SEQ ID NOS:38,32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or1130) and a VL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43, 1045-1048,1085, 1096, 1103, 1114, 1121 or 1132); a VH CDR3 (SEQ ID NOS:38, 32,319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or1130) and a VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091, 1097, 1109,1115, 1127 or 1133); a VH CDR1 (SEQ ID NOS:36, 30, 59-62, 33, 1081,1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or 1128), aVH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95,321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088,1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134) and a VLCDR1 (SEQ ID NOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113,1120, 1126 or 1131); a VH CDR1 (SEQ ID NOS:36, 30, 59-62, 33, 1081,1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or 1128), aVH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95,321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088,1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134) and a VLCDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096,1103, 1114, 1121 or 1132); a VH CDR1 (SEQ ID NOS:36, 30, 59-62, 33,1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or1128), a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74,83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082,1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134) anda VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115,1127 or 1133); a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31,65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894,1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124,1129 or 1134), a VH CDR3 (SEQ ID NOS:38, 32, 319, 35, 883-885, 1083,1089, 1094, 1101, 1107, 1112, 1119, 1125 or 1130) and a VL CDR1 (SEQ IDNOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126 or1131), a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74,83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082,1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), aVH CDR3 (SEQ ID NOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101,1107, 1112, 1119, 1125 or 1130) and a VL CDR2 (SEQ ID NOS:46, 272-275,40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121 or 1132); a VHCDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95,321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088,1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), a VH CDR3(SEQ ID NOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107,1112, 1119, 1125 or 1130) and a VL CDR3 (SEQ ID NOS:47, 41, 44,1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR1 (SEQ IDNOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110,1117, 1122, 1123 or 1128), a VL CDR1 (SEQ ID NOS:45, 253-271, 42, 1084,1090, 1095, 1102, 1108, 1113, 1120, 1126 or 1131) and a VL CDR2 (SEQ IDNOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114,1121 or 1132); a VH CDR1 (SEQ ID NOS:36, 30, 59-62, 33, 1081, 1086,1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or 1128), a VL CDR1(SEQ ID NOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120,1126 or 1131) and a VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091,1097, 1109, 1115, 1127 or 1133); a VH CDR1 (SEQ ID NOS:36, 30, 59-62,33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or1128), a VL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43, 1045-1048,1085, 1096, 1103, 1114, 1121 or 1132) and a VL CDR3 (SEQ ID NOS:47, 41,44, 1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR2 (SEQ IDNOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322,835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098,1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), a VL CDR1 (SEQ IDNOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126 or1131) and a VL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43, 1045-1048,1085, 1096, 1103, 1114, 1121 or 1132); a VH CDR2 (SEQ ID NOS:37,101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34,847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106,1111, 1116, 1118, 1124, 1129 or 1134), a VL CDR1 (SEQ ID NOS:45,253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126 or 1131) anda VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115,1127 or 1133); a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31,65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894,1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124,1129 or 1134), a VL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43,1045-1048, 1085, 1096, 1103, 1114, 1121 or 1132) and a VL CDR3 (SEQ IDNOS:47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VHCDR3 (SEQ ID NOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107,1112, 1119, 1125 or 1130), a VL CDR1 (SEQ ID NOS:45, 253-271, 42, 1084,1090, 1095, 1102, 1108, 1113, 1120, 1126 or 1131) and a VL CDR2 (SEQ IDNOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114,1121 or 1132); a VH CDR3 (SEQ ID NOS:38, 32, 319, 35, 883-885, 1083,1089, 1094, 1101, 1107, 1112, 1119, 1125 or 1130), a VL CDR1 (SEQ IDNOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126 or1131) and a VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091, 1097, 1109,1115, 1127 or 1133); a VH CDR3 (SEQ ID NOS:38, 32, 319, 35, 883-885,1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or 1130), a VL CDR2 (SEQID NOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114,1121 or 1132) and a VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091,1097, 1109, 1115, 1127 or 1133); a VH CDR1 (SEQ ID NOS:36, 30, 59-62,33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or1128), a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74,83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082,1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), aVH CDR3 (SEQ ID NOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101,1107, 1112, 1119, 1125 or 1130) and a VL CDR1 (SEQ ID NOS:45, 253-271,42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126 or 1131); a VH CDR1(SEQ ID NOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105,1110, 1117, 1122, 1123 or 1128), a VH CDR2 (SEQ ID NOS:37, 101-104, 50,114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49,886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116,1118, 1124, 1129 or 1134), a VH CDR3 (SEQ ID NOS:38, 32, 319, 35,883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or 1130) and aVL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096,1103, 1114, 1121 or 1132); a VH CDR1 (SEQ ID NOS:36, 30, 59-62, 33,1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or1128), a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74,83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082,1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), aVH CDR3 (SEQ ID NOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101,1107, 1112, 1119, 1125 or 1130) and a VL CDR3 (SEQ ID NOS:47, 41, 44,1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR1 (SEQ IDNOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110,1117, 1122, 1123 or 1128), a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114,99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49,886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116,1118, 1124, 1129 or 1134), a VL CDR1 (SEQ ID NOS:45, 253-271, 42, 1084,1090, 1095, 1102, 1108, 1113, 1120, 1126 or 1131) and a VL CDR2 (SEQ IDNOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114,1121 or 1132); a VH CDR1 (SEQ ID NOS:36, 30, 59-62, 33, 1081, 1086,1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or 1128), a VH CDR2(SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321,322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093,1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), a VL CDR1 (SEQID NOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126or 1131) and a VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091, 1097,1109, 1115, 1127 or 1133); a VH CDR1 (SEQ ID NOS:36, 30, 59-62, 33,1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or1128), a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114, 99, 100, 31, 65-74,83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082,1088, 1093, 1098, 1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), aVL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096,1103, 1114, 1121 or 1132) and a VL CDR3 (SEQ ID NOS:47, 41, 44,1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR1 (SEQ IDNOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110,1117, 1122, 1123 or 1128), a VH CDR3 (SEQ ID NOS:38, 32, 319, 35,883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or 1130), a VLCDR1 (SEQ ID NOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113,1120, 1126 or 1131) and a VL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846,43, 1045-1048, 1085, 1096, 1103, 1114, 1121 or 1132); a VH CDR1 (SEQ IDNOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110,1117, 1122, 1123 or 1128), a VH CDR3 (SEQ ID NOS:38, 32, 319, 35,883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or 1130), a VLCDR1 (SEQ ID NOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113,1120, 1126 or 1131) and a VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058,1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR1 (SEQ ID NOS:36, 30,59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122,1123 or 1128), a VH CDR3 (SEQ ID NOS:38, 32, 319, 35, 883-885, 1083,1089, 1094, 1101, 1107, 1112, 1119, 1125 or 1130), a VL CDR2 (SEQ IDNOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114,1121 or 1132) and a VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091,1097, 1109, 1115, 1127 or 1133); a VH CDR2 (SEQ ID NOS:37, 101-104, 50,114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49,886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116,1118, 1124, 1129 or 1134), a VH CDR3 (SEQ ID NOS:38, 32, 319, 35,883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or 1130), a VLCDR1 (SEQ ID NOS:45, 253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113,1120, 1126 or 1131) and a VL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846,43, 1045-1048, 1085, 1096, 1103, 1114, 1121 or 1132); a VH CDR2 (SEQ IDNOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322,835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098,1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), a VH CDR3 (SEQ IDNOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119,1125 or 1130), a VL CDR1 (SEQ ID NOS:45, 253-271, 42, 1084, 1090, 1095,1102, 1108, 1113, 1120, 1126 or 1131) and a VL CDR3 (SEQ ID NOS:47, 41,44, 1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR2 (SEQ IDNOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322,835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098,1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), a VH CDR3 (SEQ IDNOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119,1125 or 1130), a VL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43,1045-1048, 1085, 1096, 1103, 1114, 1121 or 1132) and a VL CDR3 (SEQ IDNOS:47, 41, 44, 1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VHCDR1 (SEQ ID NOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104,1105, 1110, 1117, 1122, 1123 or 1128), a VH CDR2 (SEQ ID NOS:37,101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34,847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106,1111, 1116, 1118, 1124, 1129 or 1134), a VH CDR3 (SEQ ID NOS:38, 32,319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or1130), a VL CDR1 (SEQ ID NOS:45, 253-271, 42, 1084, 1090, 1095, 1102,1108, 1113, 1120, 1126 or 1131) and a VL CDR2 (SEQ ID NOS:46, 272-275,40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121 or 1132); a VHCDR1 (SEQ ID NOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104,1105, 1110, 1117, 1122, 1123 or 1128), a VH CDR2 (SEQ ID NOS:37,101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34,847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106,1111, 1116, 1118, 1124, 1129 or 1134), a VH CDR3 (SEQ ID NOS:38, 32,319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or1130), a VL CDR1 (SEQ ID NOS:45, 253-271, 42, 1084, 1090, 1095, 1102,1108, 1113, 1120, 1126 or 1131) and a VL CDR3 (SEQ ID NOS:47, 41, 44,1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR1 (SEQ IDNOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110,1117, 1122, 1123 or 1128), a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114,99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49,886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116,1118, 1124, 1129 or 1134), a VH CDR3 (SEQ ID NOS:38, 32, 319, 35,883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125 or 1130), a VLCDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096,1103, 1114, 1121 or 1132) and a VL CDR3 (SEQ ID NOS:47, 41, 44,1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR1 (SEQ IDNOS:36, 30, 59-62, 33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110,1117, 1122, 1123 or 1128), a VH CDR2 (SEQ ID NOS:37, 101-104, 50, 114,99, 100, 31, 65-74, 83-90, 95, 321, 322, 835-842, 34, 847-858, 49,886-894, 1070-1078, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116,1118, 1124, 1129 or 1134), a VL CDR1 (SEQ ID NOS:45, 253-271, 42, 1084,1090, 1095, 1102, 1108, 1113, 1120, 1126 or 1131), a VL CDR2 (SEQ IDNOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114,1121 or 1132), and a VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091,1097, 1109, 1115, 1127 or 1133); a VH CDR1 (SEQ ID NOS:36, 30, 59-62,33, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110, 1117, 1122, 1123 or1128), a VH CDR3 (SEQ ID NOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094,1101, 1107, 1112, 1119, 1125 or 1130), a VL CDR1 (SEQ ID NOS:45,253-271, 42, 1084, 1090, 1095, 1102, 1108, 1113, 1120, 1126 or 1131), aVL CDR2 (SEQ ID NOS:46, 272-275, 40, 843-846, 43, 1045-1048, 1085, 1096,1103, 1114, 1121 or 1132), and a VL CDR3 (SEQ ID NOS:47, 41, 44,1056-1058, 1091, 1097, 1109, 1115, 1127 or 1133); a VH CDR2 (SEQ IDNOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322,835-842, 34, 847-858, 49, 886-894, 1070-1078, 1082, 1088, 1093, 1098,1100, 1106, 1111, 1116, 1118, 1124, 1129 or 1134), a VH CDR3 (SEQ IDNOS:38, 32, 319, 35, 883-885, 1083, 1089, 1094, 1101, 1107, 1112, 1119,1125 or 1130), a VL CDR1 (SEQ ID NOS:45, 253-271, 42, 1084, 1090, 1095,1102, 1108, 1113, 1120, 1126 or 1131), a VL CDR2 (SEQ ID NOS:46,272-275, 40, 843-846, 43, 1045-1048, 1085, 1096, 1103, 1114, 1121 or1132), and a VL CDR3 (SEQ ID NOS:47, 41, 44, 1056-1058, 1091, 1097,1109, 1115, 1127 or 1133); or any combination thereof of the VH CDRs(SEQ ID NOS:36, 30, 59-62, 33, 37, 101-104, 50, 114, 99, 100, 31, 65-74,83-90, 95, 321, 322, 835-842, 34, 847-858, 49, 886-894 1070-1078, 38,32, 319, 35, 883-885, 1081, 1086, 1087, 1092, 1099, 1104, 1105, 1110,1117, 1122, 1123, 1128, 1082, 1088, 1093, 1098, 1100, 1106, 1111, 1116,1118, 1124, 1129, 1134, 1083, 1089, 1094, 1101, 1107, 1112, 1119, 1125and 1130) and VL CDRs (SEQ ID NOS:45, 253-271, 42, 46, 272-275, 40,843-846, 43, 1045-1048, 47, 41, 44, 1056-1058, 1084, 1090, 1095, 1102,1108, 1113, 1120, 1126, 1131, 1085, 1096, 1103, 1114, 1121, 1132, 1091,1097, 1109, 1115, 1127 and 1133) listed in Tables 5-10.

In certain embodiments, humanized anti-C10orf54 antibodies bind to aC10orf54 polypeptide, polypeptide fragment or epitope with an affinitycomparable to that of one or more of the murine monoclonal antibodiesdesignated 175A, 76E1 or 141A. The humanized anti-C10orf54 theantibodies can also comprise one, two, three or four human or humanizedframework regions of the immunoglobulin heavy chain variable regionand/or one, two, three or four human or humanized framework regions ofthe immunoglobulin light chain variable region. Also provided are heavyand/or light chain FR regions that contain one or more back-mutations inwhich a human FR residue is exchanged for the corresponding residuepresent in the parental murine heavy or light chain or another residuecomparable residue. In some aspects, the amino acid sequences for CDR1,CDR2, and CDR3 of the heavy and light chains for some of the humanizedanti-C10orf54 the antibodies can also include one or more mutations inwhich a CDR residue as identified in Tables 5-10. The amino acidsequences for FR1, FR2, FR3 and FR4 of the heavy and light chains thatcan be used for the humanized anti-C10orf54 the antibodies areidentified in Tables 5-7 and FIGS. 3-9 and 17.

In certain embodiments, a humanized antibody that binds to C10orf54(e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54epitope) comprises a VH region that comprises: (1) a VH FR1 having anamino acid sequence selected from the group consisting of SEQ ID NOS:51,105, 55, 115-121, 39, 58, and 895-902; (2) a VH FR2 having an amino acidsequence selected from the group consisting of SEQ ID NOS:52, 106, 56,122-124, 63, 64, and 323-326; (3) a VH FR3 having an amino acid sequenceselected from the group consisting of SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882, and 903-1030; and/or (4)a VH FR4 having an amino acid sequence of SEQ ID NO:54 or 320.Accordingly, in some embodiments, the humanized antibody comprises a VHregion that includes a VH FR1 having an amino acid sequence selectedfrom the group consisting of SEQ ID NOS:51, 105, 55, 115-121, 39, 58,and 895-902. In some embodiments, the humanized antibody comprises a VHregion that includes a VH FR2 having an amino acid sequence selectedfrom the group consisting of SEQ ID NOS:52, 106, 56, 122-124, 63, 64,and 323-326. In some embodiments, the humanized antibody comprises a VHregion that includes a VH FR3 having an amino acid sequence selectedfrom the group consisting of SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882, and 903-1030. In some embodiments, thehumanized antibody comprises a VH region that includes a VH FR4 havingan amino acid sequence of SEQ ID NO:54 or 320.

In certain embodiments, a humanized antibody that binds to C10orf54(e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54epitope) comprises a VL region that comprises: (1) a VL FR1 having anamino acid sequence selected from the group consisting of SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037, and 1059-1061; (2) a VL FR2 having anamino acid sequence selected from the group consisting of SEQ ID NOS:76,80, 284, 92, 1038-1044, and 1062-1067; (3) a VL FR3 having an amino acidsequence selected from the group consisting of SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068, and 1069; and/or (4) a VL FR4 having anamino acid of SEQ ID NO:78. Accordingly, in some aspects, the humanizedantibody comprises a VL region that includes a VL FR1 having an aminoacid sequence selected from the group consisting of SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037, and 1059-1061. In some aspects, thehumanized antibody comprises a VL region that includes a VL FR2 havingan amino acid sequence selected from the group consisting of SEQ IDNOS:76, 80, 284, 92, 1038-1044, and 1062-1067. In some aspects, thehumanized antibody comprises a VL region that includes a VL FR3 havingan amino acid sequence selected from the group consisting of SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068, and 1069. In someaspects, the humanized antibody comprises a VL region that includes a VLFR4 having an amino acid of SEQ ID NO:78.

In certain embodiments, a humanized antibody that binds to C10orf54(e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54epitope) comprises a VH region and a VL region, wherein the VH regionfurther comprises: (1) a VH FR1 having an amino acid sequence selectedfrom the group consisting of SEQ ID NOS:51, 105, 55, 115-121, 39, 58,and 895-902; (2) a VH FR2 having an amino acid sequence selected fromthe group consisting of SEQ ID NOS:52, 106, 56, 122-124, 63, 64, and323-326; (3) a VH FR3 having an amino acid sequence selected from thegroup consisting of SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882, and 903-1030; and/or (4) a VH FR4 having an aminoacid sequence of SEQ ID NO:54 or 320; and wherein the VL region furthercomprises: (1) a VL FR1 having an amino acid sequence selected from thegroup consisting of SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037, and1059-1061; (2) a VL FR2 having an amino acid sequence selected from thegroup consisting of SEQ ID NOS:76, 80, 284, 92, 1038-1044, and1062-1067; (3) a VL FR3 having an amino acid sequence selected from thegroup consisting of SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068, and 1069; and/or (4) a VL FR4 having an amino acid of SEQ IDNO:78.

Also provided herein are antibodies comprising one or more (e.g., one,two, three or four) VH FRs and one or more VL FRs listed in Tables 5-7.In particular, provided herein is an antibody comprising a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902) and a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902) and a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR1 (SEQ ID NOS:51,105, 55, 115-121, 39, 58 or 895-902) and a VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105,55, 115-121, 39, 58 or 895-902) and a VL FR4 (SEQ ID NO:78); a VH FR2(SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326) and a VL FR1 (SEQID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061); a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326) and a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326) and a VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR2 (SEQ ID NOS:52, 106,56, 122-124, 63, 64 or 323-326) and a VL FR4 (SEQ ID NO:78); a VH FR3(SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030) and a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030) and a VL FR2 (SEQ ID NOS:76,80, 284, 92, 1038-1044 or 1062-1067); a VH FR3 (SEQ ID NOS:53, 107-113,57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030) and a VLFR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VHFR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326) and a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061); a VH FR1 (SEQ ID NOS:51, 105,55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56,122-124, 63, 64 or 323-326) and a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326)and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251,96-98, 292-318, 327-833, 53, 859-882 or 903-1030) and a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030)and a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VHFR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030) and a VL FR4 (SEQ ID NO:78); a VH FR1(SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR2 (SEQID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR4 (SEQ IDNO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3(SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1(SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR4 (SEQ IDNO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), aVL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) anda VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR2(SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR3 (SEQID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR4 (SEQID NO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067)and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or1069); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), aVL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR4(SEQ ID NO:78); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061)and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or1069); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061) and a VL FR4 (SEQ ID NO:78); a VHFR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VL FR2 (SEQ ID NOS:76, 80,284, 92, 1038-1044 or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR4(SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061) and a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067); a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR3(SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR4(SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061) and a VL FR4 (SEQ ID NO:78); a VH FR4 (SEQ IDNO:54 or 320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069); a VH FR4 (SEQ ID NO:54 or 320), a VL FR2 (SEQ ID NOS:76,80, 284, 92, 1038-1044 or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VHFR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030) and a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037or 1059-1061); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326),a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030) and a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030) and a VL FR3 (SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105, 55,115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251,96-98, 292-318, 327-833, 53, 859-882 or 903-1030) and a VL FR4 (SEQ IDNO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4(SEQ ID NO:54 or 320) and a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR4 (SEQ ID NO:54 or 320) and a VL FR2 (SEQ ID NOS:76,80, 284, 92, 1038-1044 or 1062-1067); a VH FR1 (SEQ ID NOS:51, 105, 55,115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or 320) and a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or 320) anda VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or320) and a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320) and aVL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR1(SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VH FR4 (SEQ ID NO:54 or 320) and a VL FR3 (SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51,105, 55, 115-121, 39, 58 or 895-902), a VH FR3 (SEQ ID NOS:53, 107-113,57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320) and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VH FR4 (SEQ ID NO:54 or 320) and a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061); a VH FR2 (SEQ ID NOS:52, 106, 56,122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320) and a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63,64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or320) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068or 1069); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326),a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320) and a VL FR4(SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326),a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061)and a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VHFR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR3 (SEQID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR4 (SEQ IDNO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061) and a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061)and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121,39, 58 or 895-902), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR2 (SEQID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR4 (SEQ ID NO:54 or320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR4 (SEQ ID NO:78); aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3(SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061) and a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63,64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061)and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR2 (SEQID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR4 (SEQ ID NO:78); aVH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR3 (SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061) and a VL FR4 (SEQ ID NO:78); a VHFR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326), a VL FR2 (SEQ ID NOS:76, 80, 284,92, 1038-1044 or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067)and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or1069); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030), a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR4 (SEQ ID NO:54 or320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) anda VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069);a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR4(SEQ ID NO:54 or 320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106,56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067)and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) anda VL FR4 (SEQ ID NO:78); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251,96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ IDNO:54 or 320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) anda VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55,115-121, 39, 58 or 895-902), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR3(SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VLFR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR4 (SEQ ID NO:54 or 320), a VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3(SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or320), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or1069) and a VL FR4 (SEQ ID NO:78); a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76,80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105,55, 115-121, 39, 58 or 895-902), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284,92, 1038-1044 or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067),a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069)and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044or 1062-1067) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63,64 or 323-326), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106,56, 122-124, 63, 64 or 323-326), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061), a VL FR3 (SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VHFR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VL FR2 (SEQID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQID NO:78); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76,80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061),a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VLFR4 (SEQ ID NO:78); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251,96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQID NO:78); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VL FR2 (SEQ ID NOS:76, 80,284, 92, 1038-1044 or 1062-1067), a VL FR3 (SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VHFR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283,91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291,93, 1049-1055, 1068 or 1069); a VH FR4 (SEQ ID NO:54 or 320), a VL FR1(SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL Page146 of 256 FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) anda VL FR4 (SEQ ID NO:78); a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR3 (SEQID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4(SEQ ID NO:78); a VH FR4 (SEQ ID NO:54 or 320), a VL FR2 (SEQ ID NOS:76,80, 284, 92, 1038-1044 or 1062-1067), a VL FR3 (SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VHFR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VH FR4 (SEQ ID NO:54 or 320) and a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061); a VH FR1 (SEQ ID NOS:51,105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56,122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320) and a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320) and aVL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); aVH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2(SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VH FR4 (SEQ ID NO:54 or 320) and a VL FR4 (SEQ ID NO:78); aVH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2(SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061) and a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326),a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291,93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121,39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061) and a VL FR4 (SEQ ID NO:78); a VHFR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067)and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or1069); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3(SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105,55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56,122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR3(SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VLFR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326),a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061) and a VL FR2 (SEQ ID NOS:76, 80,284, 92, 1038-1044 or 1062-1067); a VH FR1 (SEQ ID NOS:51, 105, 55,115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR3 (SEQID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105,55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56,122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) anda VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3(SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR2 (SEQID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061) and a VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR2 (SEQ ID NOS:52, 106,56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061) and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VH FR4 (SEQ ID NO:54 or 320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291,93, 1049-1055, 1068 or 1069); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251,96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ IDNO:54 or 320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106,56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284,92, 1038-1044 or 1062-1067), and a VL FR3 (SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105, 55,115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044or 1062-1067), and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51,105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56,122-124, 63, 64 or 323-326), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283,91, 1031-1037 or 1059-1061), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291,93, 1049-1055, 1068 or 1069), and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VL FR2 (SEQ ID NOS:76,80, 284, 92, 1038-1044 or 1062-1067), a VL FR3 (SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068 or 1069), and a VL FR4 (SEQ ID NO:78); a VHFR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR3 (SEQID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067), and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98,292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76,80, 284, 92, 1038-1044 or 1062-1067), and a VL FR4 (SEQ ID NO:78); a VHFR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR3 (SEQID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069), and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51,105, 55, 115-121, 39, 58 or 895-902), a VH FR3 (SEQ ID NOS:53, 107-113,57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069), and a VL FR4(SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80,284, 92, 1038-1044 or 1062-1067), and a VL FR3 (SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105, 55,115-121, 39, 58 or 895-902), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1(SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), and a VL FR4 (SEQID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069), and a VL FR4 (SEQ ID NO:78);a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR4(SEQ ID NO:54 or 320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044or 1062-1067), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069), and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113,57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1(SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), and a VL FR3 (SEQID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067), and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106,56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1(SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR3(SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069), and a VLFR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030), a VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069), and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067), and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63,64 or 323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76,80, 284, 92, 1038-1044 or 1062-1067), and a VL FR4 (SEQ ID NO:78); a VHFR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069), and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or320), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), aVL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069),and a VL FR4 (SEQ ID NO:78); a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044or 1062-1067), and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069); a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251,96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ IDNO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067), and a VL FR4 (SEQ ID NO:78); a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061), a VL FR3 (SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068 or 1069), and a VL FR4 (SEQ ID NO:78); a VHFR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067), a VL FR3 (SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068 or 1069), and a VL FR4 (SEQ IDNO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), aVL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), a VL FR3(SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069), and a VLFR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067), a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069), and a VL FR4 (SEQ ID NO:78); a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061),a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), a VL FR3(SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069), and a VLFR4 (SEQ ID NO:78); a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067), a VL FR3 (SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068 or 1069), and a VL FR4 (SEQ IDNO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3(SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and a VL FR2 (SEQID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113,57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320), VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291,93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121,39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), VLFR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061) and aVL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), VLFR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3(SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1(SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VH FR4 (SEQ ID NO:54 or 320), VL FR2 (SEQ ID NOS:76, 80, 284, 92,1038-1044 or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113,57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320), VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113,57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1(SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061),VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR4(SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326),a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061), VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113,57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326),a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061), VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044or 1062-1067) and a VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93,1049-1055, 1068 or 1069); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39,58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061), VL FR2 (SEQ ID NOS:76, 80,284, 92, 1038-1044 or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR1(SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061), VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55,115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067), VL FR3 (SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ IDNO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061), VL FR2 (SEQ ID NOS:76, 80, 284,92, 1038-1044 or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061), VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); aVH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR3(SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067), VL FR3 (SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ IDNO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), aVH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833,53, 859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR2 (SEQ IDNOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53,107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030),a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061), VL FR2 (SEQ ID NOS:76, 80, 284,92, 1038-1044 or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ IDNOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061), VL FR3 (SEQ ID NOS:77, 276,81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3(SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067), VL FR3 (SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ IDNO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VL FR1(SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or895-902), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ ID NOS:75, 252, 79,277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284,92, 1038-1044 or 1062-1067), VL FR3 (SEQ ID NOS:77, 276, 81, 285-291,93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR4 (SEQ ID NO:54or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or1059-1061), a VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067), VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106, 56,122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1(SEQ ID NOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2(SEQ ID NOS:76, 80, 284, 92, 1038-1044 or 1062-1067), VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQID NO:78); a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or323-326), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252,79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ ID NOS:76, 80,284, 92, 1038-1044 or 1062-1067), VL FR3 (SEQ ID NOS:77, 276, 81,285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VHFR3 (SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), a VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067), VL FR3 (SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ IDNO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR3(SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318, 327-833, 53,859-882 or 903-1030), a VH FR4 (SEQ ID NO:54 or 320), VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067) and a VL FR3 (SEQ IDNOS:77, 276, 81, 285-291, 93, 1049-1055, 1068 or 1069); a VH FR1 (SEQ IDNOS:51, 105, 55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52,106, 56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113,57, 125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320), VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061), VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044or 1062-1067) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105,55, 115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56,122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320), VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044 or1062-1067), VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055, 1068or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR1 (SEQ ID NOS:51, 105, 55,115-121, 39, 58 or 895-902), a VH FR2 (SEQ ID NOS:52, 106, 56, 122-124,63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57, 125-251,96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VL FR1 (SEQ IDNOS:75, 252, 79, 277-283, 91, 1031-1037 or 1059-1061), VL FR2 (SEQ IDNOS:76, 80, 284, 92, 1038-1044 or 1062-1067), VL FR3 (SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068 or 1069) and a VL FR4 (SEQ IDNO:78); a VH FR1 (SEQ ID NOS:51, 105, 55, 115-121, 39, 58 or 895-902), aVH FR2 (SEQ ID NOS:52, 106, 56, 122-124, 63, 64 or 323-326), a VH FR4(SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061), VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044or 1062-1067), VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069) and a VL FR4 (SEQ ID NO:78); a VH FR2 (SEQ ID NOS:52, 106,56, 122-124, 63, 64 or 323-326), a VH FR3 (SEQ ID NOS:53, 107-113, 57,125-251, 96-98, 292-318, 327-833, 53, 859-882 or 903-1030), a VH FR4(SEQ ID NO:54 or 320), a VL FR1 (SEQ ID NOS:75, 252, 79, 277-283, 91,1031-1037 or 1059-1061), VL FR2 (SEQ ID NOS:76, 80, 284, 92, 1038-1044or 1062-1067), VL FR3 (SEQ ID NOS:77, 276, 81, 285-291, 93, 1049-1055,1068 or 1069) and a VL FR4 (SEQ ID NO:78); or any combination thereof ofthe VH FRs (SEQ ID NOS:51, 105, 55, 115-121, 39, 58, 895-902, 52, 106,56, 122-124, 63, 64, 323-326, 53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882 903-1030, 54 or 320) and VL FRs (SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037, 1059-1061, 76, 80, 284, 92, 1038-1044,1062-1067, 77, 276, 81, 285-291, 93, 1049-1055, 1068, 1069, or 78)listed in Tables 5-7.

In some embodiments, antibodies provided herein are antibodies that bindto C10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope), and include antibodies comprising derivatives of theVH domains, VH CDRs, VL domains, and VL CDRs described herein that bindto C10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment,C10orf54 epitope). Also provided herein are antibodies comprisingderivatives of the murine monoclonal antibody 175A, 76E1 or 141A,wherein the antibodies bind to C10orf54 (e.g., C10orf54 polypeptide,C10orf54 polypeptide fragment, C10orf54 epitope). Standard techniquesknown to those of skill in the art can be used to introduce mutations inthe nucleotide sequence encoding an antibody, or fragment thereof,provided herein, including, for example, site-directed mutagenesis andPCR-mediated mutagenesis which results in amino acid substitutions. Incertain embodiments, the derivatives include less than 25 amino acidsubstitutions, less than 20 amino acid substitutions, less than 15 aminoacid substitutions, less than 10 amino acid substitutions, less than 5amino acid substitutions, less than 4 amino acid substitutions, lessthan 3 amino acid substitutions, or less than 2 amino acid substitutionsrelative to the original molecule. In a specific embodiment, thederivatives have conservative amino acid substitutions are made at oneor more predicted non-essential amino acid residues. A “conservativeamino acid substitution” is one in which the amino acid residue isreplaced with an amino acid residue having a side chain with a similarcharge. Families of amino acid residues having side chains with similarcharges have been defined in the art. These families include amino acidswith basic side chains (e.g., lysine, arginine, histidine), acidic sidechains (e.g., aspartic acid, glutamic acid), uncharged polar side chains(e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine,cysteine), nonpolar side chains (e.g., alanine, valine, leucine,isoleucine, proline, phenylalanine, methionine, tryptophan),beta-branched side chains (e.g., threonine, valine, isoleucine) andaromatic side chains (e.g., tyrosine, phenylalanine, tryptophan,histidine). Alternatively, mutations can be introduced randomly alongall or part of the coding sequence, such as by saturation mutagenesis,and the resultant mutants can be screened for biological activity toidentify mutants that retain activity. Following mutagenesis, theencoded protein can be expressed and the activity of the protein can bedetermined.

In one embodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesan amino acid sequence that is at least 35%, at least 40%, at least 45%,at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, or atleast 99% identical to the amino acid sequence of the murine monoclonalantibody 175A, 76E1 or 141A, or an antigen-binding fragment thereof,such as a VH domain or VL domain. In one embodiment, an antibody thatbinds to C10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptidefragment, C10orf54 epitope) comprises an amino acid sequence that is atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, or at least 99% identical to anamino acid sequence depicted in SEQ ID NOS:12-29. In another embodiment,an antibody that binds to C10orf54 (e.g., C10orf54 polypeptide, C10orf54polypeptide fragment, C10orf54 epitope) comprises an amino acid sequencethat is at least 35%, at least 40%, at least 45%, at least 50%, at least55%, at least 60%, at least 65%, at least 70%, at least 75%, at least80%, at least 85%, at least 90%, at least 95%, or at least 99% identicalto an amino acid sequence depicted in Tables 5-10. In yet anotherembodiment, an antibody that binds to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesa VH CDR and/or a VL CDR amino acid sequence that is at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 99% identical to a VH CDR aminoacid sequence depicted in Tables 5-10 and/or a VL CDR amino acidsequence depicted in Tables 5-10.

In certain embodiments, the antibodies used in accordance with themethods provided herein have a high affinity for a C10orf54 polypeptide,or polypeptide fragment or epitope thereof. In one embodiment, theantibodies used in accordance with the methods provided herein have ahigher affinity for a C10orf54 antibody than known antibodies (e.g.,commercially available monoclonal antibodies discussed elsewhereherein). In a specific embodiment, the antibodies used in accordancewith the methods provided herein have a 2- to 10-fold (or more) higheraffinity for a C10orf54 antigen than a known anti-C10orf54 antibody asassessed by techniques described herein or known to one of skill in theart (e.g., a BIAcore assay). In accordance with these embodiments, theaffinity of the antibodies are, in one embodiment, assessed by a BIAcoreassay.

In a specific embodiment, an antibody that binds C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope)comprises an amino acid sequence of a VH domain and/or an amino acidsequence a VL domain encoded by a nucleotide sequence that hybridizes to(1) the complement of a nucleotide sequence encoding any one of the VHand/or VL domains depicted in Tables 2 and 4-under stringent conditions(e.g., hybridization to filter-bound DNA in 6× sodium chloride/sodiumcitrate (SSC) at about 45° C. followed by one or more washes in0.2×SSC/0.1% SDS at about 50-65° C.) under highly stringent conditions(e.g., hybridization to filter-bound nucleic acid in 6×SSC at about 45°C. followed by one or more washes in 0.1×SSC/0.2% SDS at about 68° C.),or under other stringent hybridization conditions which are known tothose of skill in the art (see, for example, Ausubel, F. M. et al.,eds., 1989, Current Protocols in Molecular Biology, Vol. I, GreenPublishing Associates, Inc. and John Wiley & Sons, Inc., New York atpages 6.3.1-6.3.6 and 2.10.3).

In another embodiment, an antibody that binds C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope) comprisesan amino acid sequence of a VH CDR or an amino acid sequence of a VL CDRencoded by a nucleotide sequence that hybridizes to the complement of anucleotide sequence encoding any one of the VH CDRs and/or VL CDRsdepicted in Tables 2 and 4-10 under stringent conditions (e.g.,hybridization to filter-bound DNA in 6×SSC at about 45° C. followed byone or more washes in 0.2×SSC/0.1% SDS at about 50-65° C.), under highlystringent conditions (e.g., hybridization to filter-bound nucleic acidin 6×SSC at about 45° C. followed by one or more washes in 0.1×SSC/0.2%SDS at about 68° C.), or under other stringent hybridization conditionswhich are known to those of skill in the art (see, for example, Ausubel,F. M. et al., eds., 1989, Current Protocols in Molecular Biology, Vol.I, Green Publishing Associates, Inc. and John Wiley & Sons, Inc., NewYork at pages 6.3.1-6.3.6 and 2.10.3)

In some embodiments, antibodies provided herein are chemically modified,e.g., by the covalent attachment of any type of molecule to theantibody. For example, but not by way of limitation, the antibodyderivatives include antibodies that have been chemically modified, e.g.,by glycosylation, acetylation, pegylation, phosphorylation, amidation,derivatization by known protecting/blocking groups, proteolyticcleavage, linkage to a cellular ligand or other protein, etc. Any ofnumerous chemical modifications may be carried out by known techniques,including, but not limited to specific chemical cleavage, acetylation,formulation, metabolic synthesis of tunicamycin, etc. Additionally, theantibody may contain one or more non-classical amino acids.

Also provided herein are antibodies that bind to C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope)which comprises a framework region known to those of skill in the art(e.g., a human or non-human fragment). The framework region may, forexample, be naturally occurring or consensus framework regions. Inspecific embodiments, the framework region of an antibody providedherein is human (see, e.g., Chothia et al., 1998, J. Mol. Biol.278:457-479 for a listing of human framework regions, which isincorporated by reference herein in its entirety). See also Kabat et al.(1991) Sequences of Proteins of Immunological Interest (U.S. Departmentof Health and Human Services, Washington, D.C.) 5th ed.

Also provided herein are antibodies that bind to C10orf54 (e.g.,C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope),the antibodies comprising the amino acid sequence of one or more of theCDRs of the murine monoclonal antibody 175A, 76E1 or 141A, includingthose also provided in Tables 5-10, or humanized variants thereof (e.g.,VH CDRs or VL CDRs of Tables 5-7), and human framework regions with oneor more amino acid substitutions at one, two, three or more of thefollowing residues: (a) rare framework residues that differ between themurine antibody framework (e.g., donor antibody framework) and the humanantibody framework (e.g., acceptor antibody framework); (b) Venier zoneresidues when differing between donor antibody framework and acceptorantibody framework; (c) interchain packing residues at the VH/VLinterface that differ between the donor antibody framework and theacceptor antibody framework; (d) canonical residues which differ betweenthe donor antibody framework and the acceptor antibody frameworksequences, particularly the framework regions crucial for the definitionof the canonical class of the murine antibody CDR loops; (e) residuesthat are adjacent to a CDR; (g) residues capable of interacting with theantigen; (h) residues capable of interacting with the CDR; and (i)contact residues between the VH domain and the VL domain. In certainembodiments, antibodies that bind to a C10orf54 antigen comprising thehuman framework regions with one or more amino acid substitutions atone, two, three or more of the above-identified residues areantagonistic C10orf54 antibodies. In certain embodiments, antibodiesthat bind to a C10orf54 antigen comprising the human framework regionswith one or more amino acid substitutions at one, two, three or more ofthe above-identified residues are agonistic C10orf54 antibodies.

Antibodies provided herein include, but are not limited to, syntheticantibodies, monoclonal antibodies, recombinantly produced antibodies,multispecific antibodies (including bi-specific antibodies), humanantibodies, humanized antibodies, camelized antibodies, chimericantibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, andfunctional fragments of any of the above. Non-limiting examples offunctional fragments include single-chain Fvs (scFv) (e.g., includingmonospecific, bispecific, etc.), Fab fragments, F(ab′) fragments, F(ab)₂fragments, F(ab′)₂ fragments, disulfide-linked Fvs (sdFv), Fd fragments,Fv fragments, diabody, triabody, tetrabody and minibody.

In particular, antibodies provided herein include immunoglobulinmolecules and immunologically active portions of immunoglobulinmolecules, e.g., molecules that contain an antigen binding site thatbind to C10orf54 (e.g., C10orf54 polypeptide, C10orf54 polypeptidefragment, C10orf54 epitope). The immunoglobulin molecules providedherein can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class(e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass ofimmunoglobulin molecule.

Variants and derivatives of antibodies include antibody functionalfragments that retain the ability to bind to C10orf54 (e.g., C10orf54polypeptide, C10orf54 polypeptide fragment, C10orf54 epitope). Exemplaryfunctional fragments include Fab fragments (an antibody fragment thatcontains the antigen-binding domain and comprises a light chain and partof a heavy chain bridged by a disulfide bond); Fab′ (an antibodyfragment containing a single anti-binding domain comprising an Fab andan additional portion of the heavy chain through the hinge region);F(ab′)₂ (two Fab′ molecules joined by interchain disulfide bonds in thehinge regions of the heavy chains; the Fab′ molecules may be directedtoward the same or different epitopes); a bispecific Fab (a Fab moleculehaving two antigen binding domains, each of which may be directed to adifferent epitope); a single chain Fab chain comprising a variableregion, also known as, a sFv (the variable, antigen-bindingdeterminative region of a single light and heavy chain of an antibodylinked together by a chain of 10-25 amino acids); a disulfide-linked Fv,or dsFv (the variable, antigen-binding determinative region of a singlelight and heavy chain of an antibody linked together by a disulfidebond); a camelized VH (the variable, antigen-binding determinativeregion of a single heavy chain of an antibody in which some amino acidsat the VH interface are those found in the heavy chain of naturallyoccurring camel antibodies); a bispecific sFv (a sFv or a dsFv moleculehaving two antigen-binding domains, each of which may be directed to adifferent epitope); a diabody (a dimerized sFv formed when the VH domainof a first sFv assembles with the VL domain of a second sFv and the VLdomain of the first sFv assembles with the VH domain of the second sFv;the two antigen-binding regions of the diabody may be directed towardsthe same or different epitopes); and a triabody (a trimerized sFv,formed in a manner similar to a diabody, but in which threeantigen-binding domains are created in a single complex; the threeantigen binding domains may be directed towards the same or differentepitopes). Derivatives of antibodies also include one or more CDRsequences of an antibody combining site. The CDR sequences may be linkedtogether on a scaffold when two or more CDR sequences are present. Incertain embodiments, the antibody comprises a single-chain Fv (“scFv”).scFvs are antibody fragments comprising the VH and VL domains of anantibody, wherein these domains are present in a single polypeptidechain. Generally, the scFv polypeptide further comprises a polypeptidelinker between the VH and VL domains which enables the scFv to form thedesired structure for antigen binding. For a review of scFvs seePluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113,Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315 (1994).

The antibodies provided herein may be monospecific, bispecific,trispecific or of greater multispecificity. Multispecific antibodies maybe specific for different epitopes of a C10orf54 polypeptide or may bespecific for both a C10orf54 polypeptide as well as for a heterologousepitope, such as a heterologous polypeptide or solid support material.In specific embodiments, the antibodies provided herein are monospecificfor a given epitope of a C10orf54 polypeptide and do not bind to otherepitopes.

Also provided herein are fusion proteins comprising an antibody providedherein that binds to a C10orf54 antigen and a heterologous polypeptide.In some embodiments, the heterologous polypeptide to which the antibodyis fused is useful for targeting the antibody to cells having cellsurface-expressed C10orf54.

Also provided herein are panels of antibodies that bind to a C10orf54antigen. In specific embodiments, panels of antibodies have differentassociation rate constants different dissociation rate constants,different affinities for C10orf54 antigen, and/or differentspecificities for a C10orf54 antigen. In some embodiments, the panelscomprise or consist of about 10, about 25, about 50, about 75, about100, about 125, about 150, about 175, about 200, about 250, about 300,about 350, about 400, about 450, about 500, about 550, about 600, about650, about 700, about 750, about 800, about 850, about 900, about 950,or about 1000 antibodies or more. Panels of antibodies can be used, forexample, in 96 well or 384 well plates, such as for assays such asELISAs.

Antibody Conjugates and Fusion Proteins

In some embodiments, antibodies provided herein are conjugated orrecombinantly fused to a diagnostic, detectable or therapeutic agent orany other molecule. The conjugated or recombinantly fused antibodies canbe useful, e.g., for monitoring or prognosing the onset, development,progression and/or severity of a C10orf54-mediated disease as part of aclinical testing procedure, such as determining the efficacy of aparticular therapy.

Such diagnosis and detection can accomplished, for example, by couplingthe antibody to detectable substances including, but not limited to,various enzymes, such as, but not limited to, horseradish peroxidase,alkaline phosphatase, beta-galactosidase, or acetylcholinesterase;prosthetic groups, such as, but not limited to, streptavidin/biotin andavidin/biotin; fluorescent materials, such as, but not limited to,umbelliferone, fluorescein, fluorescein isothiocynate, rhodamine,dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin;luminescent materials, such as, but not limited to, luminol;bioluminescent materials, such as but not limited to, luciferase,luciferin, and aequorin; chemiluminescent material, such as but notlimited to, an acridinium based compound or a HALOTAG; radioactivematerials, such as, but not limited to, iodine (¹³¹I, ¹²⁵I, ¹²³I, and¹²¹I), carbon (¹⁴C), sulfur (³⁵S), tritium (³H), indium (¹¹⁵In, ¹¹³In,¹¹²In, and ¹¹¹In), technetium (⁹⁹Tc), thallium (²⁰¹Ti), gallium (⁶⁸Ga,⁶⁷Ga), palladium (¹⁰³Pd), molybdenum (⁹⁹Mo), xenon (¹³³Xe), fluorine(¹⁸F), ¹⁵³Sm, ¹⁷⁷Lu, ¹⁵⁹Gd, ¹⁴⁹Pm, ¹⁴⁰La, ¹⁷⁵Yb, ¹⁶⁶Ho, ⁹⁰Y, ⁴⁷Sc,¹⁸⁶Re, ¹⁸⁸Re, ¹⁴²Pr, ¹⁰⁵Rh, ⁹⁷Ru, ⁶⁸Ge, ⁵⁷Co, ⁶⁵Zn, ⁸⁵Sr, ³²P, ¹⁵³Gd,¹⁶⁹Yb, ⁵¹Cr ⁵⁴Mn, ⁷⁵Se, ¹¹³Sn, and ¹¹⁷Sn; and positron emitting metalsusing various positron emission tomographies, and non-radioactiveparamagnetic metal ions.

Also provided herein are antibodies that are conjugated or recombinantlyfused to a therapeutic moiety (or one or more therapeutic moieties), aswell as uses thereof. The antibody may be conjugated or recombinantlyfused to a therapeutic moiety, such as a cytotoxin, e.g., a cytostaticor cytocidal agent, a therapeutic agent or a radioactive metal ion,e.g., alpha-emitters. A cytotoxin or cytotoxic agent includes any agentthat is detrimental to cells. Therapeutic moieties include, but are notlimited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine,6-thioguanine, cytarabine, 5-fluorouracil decarbazine); alkylatingagents (e.g., mechlorethamine, thioepa chlorambucil, melphalan,carmustine (BCNU) and lomustine (CCNU), cyclothosphamide, busulfan,dibromomannitol, streptozotocin, mitomycin C, and cisdichlorodiamineplatinum (II) (DDP), and cisplatin); anthracyclines (e.g., daunorubicin(formerly daunomycin) and doxorubicin); antibiotics (e.g., d actinomycin(formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC));Auristatin molecules (e.g., auristatin PHE, auristatin F, monomethylauristatin E, bryostatin 1, and solastatin 10; see Woyke et al.,Antimicrob. Agents Chemother. 46:3802-8 (2002), Woyke et al.,Antimicrob. Agents Chemother. 45:3580-4 (2001), Mohammad et al.,Anticancer Drugs 12:735-40 (2001), Wall et al., Biochem. Biophys. Res.Commun. 266:76-80 (1999), Mohammad et al., Int. J. Oncol. 15:367-72(1999), all of which are incorporated herein by reference); hormones(e.g., glucocorticoids, progestins, androgens, and estrogens),DNA-repair enzyme inhibitors (e.g., etoposide or topotecan), kinaseinhibitors (e.g., compound ST1571, imatinib mesylate (Kantarjian et al.,Clin Cancer Res. 8(7):2167-76 (2002)); cytotoxic agents (e.g.,paclitaxel, cytochalasin B, gramicidin D, ethidium bromide, emetine,mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicin,doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone,mithramycin, actinomycin D, 1-dehydrotestosterone, glucorticoids,procaine, tetracaine, lidocaine, propranolol, and puromycin and analogsor homologs thereof and those compounds disclosed in U.S. Pat. Nos.6,245,759, 6,399,633, 6,383,790, 6,335,156, 6,271,242, 6,242,196,6,218,410, 6,218,372, 6,057,300, 6,034,053, 5,985,877, 5,958,769,5,925,376, 5,922,844, 5,911,995, 5,872,223, 5,863,904, 5,840,745,5,728,868, 5,648,239, 5,587,459); famesyl transferase inhibitors (e.g.,R115777, BMS-214662, and those disclosed by, for example, U.S. Pat. Nos.6,458,935, 6,451,812, 6,440,974, 6,436,960, 6,432,959, 6,420,387,6,414,145, 6,410,541, 6,410,539, 6,403,581, 6,399,615, 6,387,905,6,372,747, 6,369,034, 6,362,188, 6,342,765, 6,342,487, 6,300,501,6,268,363, 6,265,422, 6,248,756, 6,239,140, 6,232,338, 6,228,865,6,228,856, 6,225,322, 6,218,406, 6,211,193, 6,187,786, 6,169,096,6,159,984, 6,143,766, 6,133,303, 6,127,366, 6,124,465, 6,124,295,6,103,723, 6,093,737, 6,090,948, 6,080,870, 6,077,853, 6,071,935,6,066,738, 6,063,930, 6,054,466, 6,051,582, 6,051,574, and 6,040,305);topoisomerase inhibitors (e.g., camptothecin; irinotecan; SN-38;topotecan; 9-aminocamptothecin; GG-211 (GI 147211); DX-8951f; IST-622;rubitecan; pyrazoloacridine; XR-5000; saintopin; UCE6; UCE1022;TAN-1518A; TAN 1518B; KT6006; KT6528; ED-110; NB-506; ED-110; NB-506;and rebeccamycin); bulgarein; DNA minor groove binders such as Hoeschtdye 33342 and Hoechst dye 33258; nitidine; fagaronine; epiberberine;coralyne; beta-lapachone; BC-4-1; bisphosphonates (e.g., alendronate,cimadronte, dodronate, tiludronate, etidronate, ibandronate,neridronate, olpandronate, risedronate, piridronate, pamidronate,zolendronate) HMG-CoA reductase inhibitors, (e.g., lovastatin,simvastatin, atorvastatin, pravastatin, fluvastatin, statin,cerivastatin, lescol, lupitor, rosuvastatin and atorvastatin); antisenseoligonucleotides (e.g., those disclosed in the U.S. Pat. Nos. 6,277,832,5,998,596, 5,885,834, 5,734,033, and 5,618,709); adenosine deaminaseinhibitors (e.g., Fludarabine phosphate and 2-Chlorodeoxyadenosine);ibritumomab tiuxetan (Zevalin®); tositumomab (Bexxar®)) andpharmaceutically acceptable salts, solvates, clathrates, and prodrugsthereof.

Further, an antibody provided herein may be conjugated or recombinantlyfused to a therapeutic moiety or drug moiety that modifies a givenbiological response. Therapeutic moieties or drug moieties are not to beconstrued as limited to classical chemical therapeutic agents. Forexample, the drug moiety may be a protein, peptide, or polypeptidepossessing a desired biological activity. Such proteins may include, forexample, a toxin such as abrin, ricin A, pseudomonas exotoxin, choleratoxin, or diphtheria toxin; a protein such as tumor necrosis factor,γ-interferon, α-interferon, nerve growth factor, platelet derived growthfactor, tissue plasminogen activator, an apoptotic agent, e.g., TNF-γ,TNF-γ, AIM I (see, International Publication No. WO 97/33899), AIM II(see, International Publication No. WO 97/34911), Fas Ligand (Takahashiet al., 1994, J. Immunol., 6:1567-1574), and VEGF (see, InternationalPublication No. WO 99/23105), an anti-angiogenic agent, e.g.,angiostatin, endostatin or a component of the coagulation pathway (e.g.,tissue factor); or, a biological response modifier such as, for example,a lymphokine (e.g., interferon gamma, interleukin-1 (“IL-1”),interleukin-2 (“IL-2”), interleukin-5 (“IL-5”), interleukin-6 (“IL-6”),interleukin-7 (“IL-7”), interleukin 9 (“IL-9”), interleukin-10(“IL-10”), interleukin-12 (“IL-12”), interleukin-15 (“IL-15”),interleukin-23 (“IL-23”), granulocyte macrophage colony stimulatingfactor (“GM-CSF”), and granulocyte colony stimulating factor (“G-CSF”)),or a growth factor (e.g., growth hormone (“GH”)), or a coagulation agent(e.g., calcium, vitamin K, tissue factors, such as but not limited to,Hageman factor (factor XII), high-molecular-weight kininogen (HMWK),prekallikrein (PK), coagulation proteins-factors II (prothrombin),factor V, XIIa, VIII, XIIIa, XI, XIa, IX, IXa, X, phospholipid, andfibrin monomer).

Also provided herein are antibodies that are recombinantly fused orchemically conjugated (covalent or non-covalent conjugations) to aheterologous protein or polypeptide (or fragment thereof, for example,to a polypeptide of about 10, about 20, about 30, about 40, about 50,about 60, about 70, about 80, about 90 or about 100 amino acids) togenerate fusion proteins, as well as uses thereof. In particular,provided herein are fusion proteins comprising an antigen-bindingfragment of an antibody provided herein (e.g., a Fab fragment, Fdfragment, Fv fragment, F(ab)₂ fragment, a VH domain, a VH CDR, a VLdomain or a VL CDR) and a heterologous protein, polypeptide, or peptide.In one embodiment, the heterologous protein, polypeptide, or peptidethat the antibody is fused to is useful for targeting the antibody to aparticular cell type, such as a cell that expresses C10orf54 or anC10orf54 receptor. For example, an antibody that binds to a cell surfacereceptor expressed by a particular cell type (e.g., an immune cell) maybe fused or conjugated to a modified antibody provided herein.

A conjugated or fusion protein can comprise any antibody provided hereindescribed herein and a heterologous polypeptide. In one embodiment, aconjugated or fusion protein provided herein comprises the VH or VLdomain of any one of the murine monoclonal antibodies 175A, 76E1 or141A, as depicted in Table 2, and a heterologous polypeptide. In anotherembodiment, a conjugated or fusion protein provided herein comprises aVH domain having the amino acid sequence of any one of the VH domainsdepicted in Tables 5-10, and/or a VL domain having the amino acidsequence of any one of the VL domains depicted Tables 5-10, and aheterologous polypeptide. In another embodiment, a conjugated or fusionprotein provided herein comprises one or more VH CDRs having the aminoacid sequence of any one of the VH CDRs depicted in Tables 5-10, and aheterologous polypeptide. In another embodiment, a conjugated or fusionprotein comprises one or more VL CDRs having the amino acid sequence ofany one of the VL CDRs depicted in Tables 5-10, and a heterologouspolypeptide. In another embodiment, a conjugated or fusion proteinprovided herein comprises at least one VH domain and at least one VLdomain depicted in Tables 5-10, and a heterologous polypeptide. In yetanother embodiment, a conjugated or fusion protein provided hereincomprises at least one VH CDR and at least one VL CDR depicted in Tables5-10, and a heterologous polypeptide.

In addition, an antibody provided herein can be conjugated totherapeutic moieties such as a radioactive metal ion, such asalpha-emitters such as ²¹³Bi or macrocyclic chelators useful forconjugating radiometal ions, including but not limited to, ¹³¹In, ¹³¹LU,¹³¹Y, ¹³¹Ho, ¹³¹Sm, to polypeptides. In certain embodiments, themacrocyclic chelator is 1,4,7,10-tetraazacyclododecane-N, N′,N″,N′″-tetraacetic acid (DOTA) which can be attached to the antibody via alinker molecule. Such linker molecules are commonly known in the art anddescribed in Denardo et al., 1998, Clin Cancer Res. 4(10):2483-90;Peterson et al., 1999, Bioconjug. Chem. 10(4):553-7; and Zimmerman etal., 1999, Nucl. Med. Biol. 26(8):943-50, each incorporated by referencein their entireties.

Moreover, antibodies provided herein can be fused to marker sequences,such as a peptide to facilitate purification. In specific embodiments,the marker amino acid sequence is a hexa-histidine peptide, such as thetag provided in a pQE vector (QIAGEN, Inc.), among others, many of whichare commercially available. As described in Gentz et al., 1989, Proc.Natl. Acad. Sci. USA 86:821-824, for instance, hexa-histidine providesfor convenient purification of the fusion protein. Other peptide tagsuseful for purification include, but are not limited to, thehemagglutinin (“HA”) tag, which corresponds to an epitope derived fromthe influenza hemagglutinin protein (Wilson et al., 1984, Cell 37:767),and the “FLAG” tag.

Methods for fusing or conjugating therapeutic moieties (includingpolypeptides) to antibodies are well known, see, e.g., Amon et al.,“Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”,in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp.243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For DrugDelivery”, in Controlled Drug Delivery (2nd Ed.), Robinson et al.(eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “AntibodyCarriers Of Cytotoxic Agents In Cancer Therapy: A Review”, in MonoclonalAntibodies 84: Biological And Clinical Applications, Pinchera et al.(eds.), pp. 475-506 (1985); “Analysis, Results, And Future ProspectiveOf The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy”, inMonoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al.(eds.), pp. 303-16 (Academic Press 1985), Thorpe et al., 1982, Immunol.Rev. 62:119-58; U.S. Pat. Nos. 5,336,603, 5,622,929, 5,359,046,5,349,053, 5,447,851, 5,723,125, 5,783,181, 5,908,626, 5,844,095, and5,112,946; EP 307,434; EP 367,166; EP 394,827; PCT publications WO91/06570, WO 96/04388, WO 96/22024, WO 97/34631, and WO 99/04813;Ashkenazi et al., Proc. Natl. Acad. Sci. USA, 88: 10535-10539, 1991;Traunecker et al., Nature, 331:84-86, 1988; Zheng et al., J. Immunol.,154:5590-5600, 1995; Vil et al., Proc. Natl. Acad. Sci. USA,89:11337-11341, 1992, which are incorporated herein by reference intheir entireties.

Fusion proteins may be generated, for example, through the techniques ofgene-shuffling, motif-shuffling, exon-shuffling, and/or codon-shuffling(collectively referred to as “DNA shuffling”). DNA shuffling may beemployed to alter the activities of antibodies provided herein (e.g.,antibodies with higher affinities and lower dissociation rates). See,generally, U.S. Pat. Nos. 5,605,793, 5,811,238, 5,830,721, 5,834,252,and 5,837,458; Patten et al., 1997, Curr. Opinion Biotechnol. 8:724-33;Harayama, 1998, Trends Biotechnol. 16(2):76-82; Hansson et al., 1999, J.Mol. Biol. 287:265-76; and Lorenzo and Blasco, 1998, Biotechniques24(2):308-313 (each of these patents and publications are herebyincorporated by reference in its entirety). Antibodies, or the encodedantibodies, may be altered by being subjected to random mutagenesis byerror-prone PCR, random nucleotide insertion or other methods prior torecombination. A polynucleotide encoding an antibody provided herein maybe recombined with one or more components, motifs, sections, parts,domains, fragments, etc. of one or more heterologous molecules.

An antibody provided herein can also be conjugated to a second antibodyto form an antibody heteroconjugate as described in U.S. Pat. No.4,676,980, which is incorporated herein by reference in its entirety.

The therapeutic moiety or drug conjugated or recombinantly fused to anantibody provided herein that binds to a C10orf54 antigen should bechosen to achieve the desired prophylactic or therapeutic effect(s). Incertain embodiments, the antibody is a modified antibody. A clinician orother medical personnel should consider the following when deciding onwhich therapeutic moiety or drug to conjugate or recombinantly fuse toan antibody provided herein: the nature of the disease, the severity ofthe disease, and the condition of the subject.

Antibodies provided herein may also be attached to solid supports, whichare particularly useful for immunoassays or purification of the targetantigen. Such solid supports include, but are not limited to, glass,cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride orpolypropylene.

Antibody-Drug Conjugate (ADC)

In some embodiments, provided herein are antibody-drug conjugates,including an antibody-drug conjugate of the following formulas (Ia) and(Ib):

or a pharmaceutically acceptable salt thereof;wherein:

-   A is an antibody or antibody fragment;-   the two depicted cysteine residues are from an opened    cysteine-cysteine disulfide bond in A;-   each X and X′ is independently O, S, NH, or NR¹ wherein R¹ is C₁₋₆    alkyl;-   W_(a) is ═N—, ═CH—, ═CHCH₂—, ═C(R²)—, or ═CHCH(R²)—; W_(b)—NH—,    —N(R¹)—, —CH₂—, —CH₂—NH—, —CH₂—N(R¹)—, —CH₂CH₂—, —CH(R²)—, or    —CH₂CH(R²)—; wherein R¹ and R² are independently C₁₋₆ alkyl;-   CTX is a cytotoxin;-   R is any chemical group; or R is absent;-   each L¹, L² and L³ is independently a linker selected from the group    consisting of —O—, —C(O)—, —S—, —S(O)—, —S(O)₂—, —NH—, —NCH₃—,    —(CH₂)_(q)—, —NH(CH₂)₂NH—, —OC(O)—, —CO₂—, —NHCH₂CH₂C(O)—,    —C(O)NHCH₂CH₂NH—, —NHCH₂C(O)—, —NHC(O)—, —C(O)NH—, —NCH₃C(O)—,    —C(O)NCH₃—, —(CH₂CH₂O)_(p), —(CH₂CH₂O)_(p)CH₂CH₂—,    —CH₂CH₂—(CH₂CH₂O)_(p)—, —OCH(CH₂O—)₂, -(AA)_(r)-, cyclopentanyl,    cyclohexanyl, unsubstituted phenylenyl, and phenylenyl substituted    by 1 or 2 substituents selected from the group consisting of halo,    CF₃—, CF₃O—, CH₃O—, —C(O)OH, —C(O)OC₁₋₃ alkyl, —C(O)CH₃, —CN, —NH—,    —NH₂, —O—, —OH, —NHCH₃, —N(CH₃)₂, and C₁₋₃ alkyl;-   a, b and c are each independently an integer of 0, 1, 2 or 3,    provided that at least one of a, b or c is 1;-   each k and k′ is independently an integer of 0 or 1;-   each p is independently an integer of 1 to 14;-   each q is independently an integer from 1 to 12;-   each AA is independently an amino acid;-   each r is 1 to 12;-   m is an integer of 1 to 4;-   n is an integer of 1 to 4; and-   the    bond represents a single or a double bond.

In certain embodiments of the antibody-drug conjugate of formula (Ib), Ris selected from the group consisting of W, (L¹)_(a), (L²)_(b),(L³)_(c), Z, W-(L¹)_(a)-(L²)_(b)-(L³)_(c), (L¹)_(a)-(L²)_(b)-(L³)_(c)-Z,and W-(L¹)_(a)-(L²)_(b)-(L³)_(c)-Z, as defined herein. In certainembodiments, R is selected from the group consisting of W, (L¹)_(a),(L²)_(b), (L³)_(c), and W-(L¹)_(a)-(L²)_(b)-(L³)_(c). In certainembodiments, R is selected from the group consisting of Z,(L¹)_(a)-(L²)_(b)-(L³)_(c)-Z, and W-(L¹)_(a)-(L²)_(b)-(L³)_(c)-Z.

In certain embodiments of the antibody-drug conjugate of formula (Ib), Ris a detectable probe. In certain embodiments, R is a fluorophore,chromophore, radiolabel, enzyme, ligand, antibody or antibody fragment.In certain embodiments, R is a ligand (e.g., a ligand specific for areceptor on a tumor cell, such as a prostate specific membrane antigen,or a virally infected cell, such as an HIV infected cell).

In certain embodiments of the antibody-drug conjugate of formula (Ib), Ris bonded to the rest of the linker molecule via an amide, an N—(C₁₋₆alkyl)amide, a carbamate, an N—(C₁₋₆ alkyl)carbamate, an amine, anN—(C₁₋₆ alkyl)amine, an ether, a thioether, an urea, an N—(C₁₋₆alkyl)urea, or an N,N-di(C₁₋₆ alkyl)urea bond.

In certain embodiments of the antibody-drug conjugate of formula (Ia) or(Ib), each L¹, L² and L³ is independently selected from the groupconsisting of —NHC(O)—, —C(O)NH—, —(CH₂CH₂O)_(p), —(CH₂CH₂O)_(p)CH₂CH₂—,—CH₂CH₂—(CH₂CH₂O)_(p)—, —OCH(CH₂O—)₂, -(AA)_(r)-, unsubstitutedphenylenyl, and phenylenyl substituted by 1 or 2 substituents selectedfrom the group consisting of halo, CF₃—, CF₃O—, CH₃O—, —C(O)OH,—C(O)OC₁₋₃ alkyl, —C(O)CH₃, —CN, —NH—, —NH₂, —O—, —OH, —NHCH₃, —N(CH₃)₂,and C₁₋₃ alkyl; where a, b and c are each independently 0 or 1; and eachp and r is independently 1, 2 or 3. In certain embodiments, one or moreof the L¹, L2 and L³ is -(AA)_(r)-, wherein -(AA)_(r)- is ValCit (e.g.,the first amino acid is Valine, the second amino acid is Citrulline, andr is 1). In certain embodiments, one or more of the L¹, L² and L³ is-(AA)_(r)-, wherein -(AA)_(r)- is ValAla (e.g., the first amino acid isValine, the second amino acid is Alanine, and r is 1). In certainembodiments, one or more of the L¹, L2 and L³ is phenylenyl substitutedby —C(O)OH and —NH₂. In certain embodiments, one or more of the L¹, L²and L³ is phenylenyl substituted by —C(O)O— and —NH—. In certainembodiments, one or more of the L¹, L² and L³ is phenylenyl substitutedby —OC(O)— and —NH—. In certain embodiments, one or more of the L¹, L²and L³ is phenylenyl substituted by —O— and —NH—. In certainembodiments, one or more of the L¹, L² and L³ is para aminobenzyl (PAB),which is optionally substituted with —C(O)O—, —OC(O)— or —O—. In certainembodiments, L¹ is —(CH₂)_(q)—, L² is absent, L³ is absent, and the CTXis bonded to (L¹)_(a)-(L²)_(b)-(L³)_(c) via an amide bond. In certainembodiments, L¹ is —(CH₂)_(q)—, L² is —(OCH₂CH₂)_(p)—, L³ is absent, andthe CTX is bonded to (L¹)_(a)-(L²)_(b)-(L³)_(c) via an amide bond. Incertain embodiments, L¹ is —(CH₂CH₂O)_(p)—, L² is —(CH₂)_(q)—, L³ isabsent, and the CTX is bonded to (L¹)_(a)-(L²)_(b)-(L³)_(c) via an amidebond. In certain embodiments, each L¹ is independently selected from thegroup consisting of —(CH₂CH₂O)_(p)CH₂CH₂— and —CH₂CH₂—(CH₂CH₂O)_(p)—, L²is absent, L³ is absent, and the CTX is bonded to (L¹)_(a)-(L²)-(L³)_(c)via an amide bond. In certain embodiments, each L¹ is independentlyselected from the group consisting of —(CH₂)_(q)—, —(CH₂CH₂O)_(p),—(CH₂CH₂O)_(p)CH₂CH₂₂—, —CH₂CH₂—(CH₂CH₂O)_(p)—, and —C(O)—, L² isVal-Cit, L³ is PAB, and the CTX is bonded to (L¹)_(a)-(L²)-(L³)_(c) viaan amide bond. In certain embodiments, each L¹ is independently selectedfrom the group consisting of —(CH₂)_(q)—, —(CH₂CH₂O)_(p),—(CH₂CH₂O)_(p)CH₂CH₂—, —CH₂CH₂—(CH₂CH₂O)_(p)—, and —C(O)—, L² isVal-Cit, L³ is PAB, and the CTX is bonded to (L¹)_(a)-(L²)_(b)-(L³)_(c)via an amide bond. In certain embodiments, each L¹ is independentlyselected from the group consisting of —(CH₂)_(q)—, —(CH₂CH₂O)_(p),—(CH₂CH₂O)_(p)CH₂CH₂—, —CH₂CH—(CH₂CH₂O)_(p)—, and —C(O)—, L² is Val-Ala,L³ is PAB, and the CTX is bonded to (L¹)_(a)-(L²)_(b)-(L³)_(c) via anamide bond.

In certain embodiments of the antibody-drug conjugate of formula (Ia) or(Ib), CTX is selected from a from the group consisting of a tubulinstabilizer, a tubulin destabilizer, a DNA alkylator, a DNA minor groovebinder, a DNA intercalator, a topoisomerase I inhibitor, a topoisomeraseII inhibitor, a gyrase inhibitor, a protein synthesis inhibitor, aproteosome inhibitor, and an anti-metabolite.

In certain embodiments of the antibody-drug conjugate of formula (Ia) or(Ib), the CTX is a chemotherapeutic agent. Those of ordinary skill inthe art will be aware of appropriate chemotherapeutic agents asdisclosed, for example, in Chu, E., DeVite, V. T., 2012, Physicians'Cancer Chemotherapy Drug Manual 2012 (Jones & Bartlett LearningOncology), and similar documents.

In certain embodiments, the CTX may be any FDA-approved chemotherapeuticagent. In certain embodiments, the CTX may be any FDA-approvedchemotherapeutic agent available for cancer treatment.

In certain embodiments, the CTX is selected from the group consisting ofan alkylating agents, an anthracyclines, a cytoskeletal disrupters(taxanes), an epothilones, an histone deacetylase Inhibitor (HDAC), aninhibitor of Topoisomerase I, an Inhibitor of Topoisomerase II, a kinaseinhibitor, a monoclonal antibodies, a nucleotide analog, a peptideantibiotic, a platinum-based agent, a retinoids, a Vinca alkaloid or aderivative thereof, and radioisotope.

In certain embodiments, the CTX is selected from the group consisting ofActinomycin, all-trans retinoic acid, Azacitidine, Azathioprine,Bleomycin, Bortezomib, Carboplatin, Capecitabine, Cisplatin,Chlorambucil, Cyclophosphamide, Cytarabine, Daunorubicin, Docetaxel,Doxifluridine, Doxorubicin, Epirubicin, Epothilone, Etoposide,Fluorouracil, Gemcitabine, Hydroxyurea, Idarubicin, Imatinib,Irinotecan, Mechlorethamine, Mercaptopurine, Methotrexate, Mitoxantrone,Oxaliplatin, Paclitaxel, Pemetrexed, Teniposide, Tioguanine, Topotecan,Valrubicin, Vinblastine, Vincristine, Vindesine, and Vinorelbine.

In certain embodiments, the CTX is selected from the group consisting ofa tubulin stabilizer, a tubulin destabilizer, a DNA alkylator, a DNAminor groove binder, a DNA intercalator, a topoisomerase I inhibitor, atopoisomerase II inhibitor, a gyrase inhibitor, a protein synthesisinhibitor, a proteosome inhibitor, and an anti-metabolite.

In certain embodiments, the CTX is selected from the group consisting ofActinomycin D, Amonafide, an auristatin, benzophenone, benzothiazole, acalicheamicin, Camptothecin, CC-1065 (NSC 298223), Cemadotin,Colchicine, Combretastatin A4, Dolastatin, Doxorubicin, Elinafide,Emtansine (DM1), Etoposide, KF-12347 (Leinamycin), a maytansinoid,Methotrexate, Mitoxantrone, Nocodazole, Proteosome Inhibitor 1 (PSI 1),Roridin A, T-2 Toxin (trichothecene analog), Taxol, a tubulysin,Velcade®, and Vincristine. In certain embodiments, the CTX is anauristatin, a calicheamicin, a maytansinoid, or a tubulysin.

In certain embodiments, the CTX is monomethylauristatin E (MMAE),monomethylauristatin F (MMAF), a pyrrolobenzodiazepine (PDB),calicheamicin γ, mertansine, or tubulysin T2. In certain embodiments,the CTX is MMAE or MMAF. In certain embodiments, the CTX is a PDB. Incertain embodiments, the CTX is tubulysin T2. In certain embodiments,the CTX is tubulysin T3, or tubulysin T4, the structures for which areprovided below:

Pharmaceutical Compositions

Therapeutic formulations containing one or more of the antibodiesprovided herein can be prepared for storage by mixing the antibodyhaving the desired degree of purity with optional physiologicallyacceptable carriers, excipients or stabilizers (Remington'sPharmaceutical Sciences (1990) Mack Publishing Co., Easton, Pa.), in theform of lyophilized formulations or aqueous solutions. Acceptablecarriers, excipients, or stabilizers are nontoxic to recipients at thedosages and concentrations employed, and include buffers such asphosphate, citrate, and other organic acids; antioxidants includingascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides, and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

The antibodies provided herein can also, for example, be formulated inliposomes. Liposomes containing the molecule of interest are prepared bymethods known in the art, such as described in Epstein et al. (1985)Proc. Natl. Acad. Sci. USA 82:3688; Hwang et al. (1980) Proc. Natl.Acad. Sci. USA 77:4030; and U.S. Pat. Nos. 4,485,045 and 4,544,545.Liposomes with enhanced circulation time are disclosed in U.S. Pat. No.5,013,556.

Particularly useful immunoliposomes can be generated by the reversephase evaporation method with a lipid composition containingphosphatidylcholine, cholesterol and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab′ fragments of an antibody provided herein can beconjugated to the liposomes as described in Martin et al. (1982) J.Biol. Chem. 257:286-288 via a disulfide interchange reaction. Achemotherapeutic agent (such as Doxorubicin) is optionally containedwithin the liposome; See Gabizon et al., (1989) J. National Cancer Inst.81(19):1484.

Formulations, such as those described herein, can also contain more thanone active compound as necessary for the particular indication beingtreated. In certain embodiments, formulations comprise an antibodyprovided herein and one or more active compounds with complementaryactivities that do not adversely affect each other. Such molecules aresuitably present in combination in amounts that are effective for thepurpose intended. For example, an antibody provided herein can becombined with one or more other therapeutic agents. Such combinedtherapy can be administered to the patient serially or simultaneously orin sequence.

An antibody provided herein can also be entrapped in microcapsuleprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsule and poly-(methylmethacylate) microcapsule,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences (1990) Mack Publishing Co., Easton,Pa.

The formulations to be used for in vivo administration can be sterile.This is readily accomplished by filtration through, e.g., sterilefiltration membranes.

Sustained-release preparations can also be prepared. Suitable examplesof sustained-release preparations include semipermeable matrices ofsolid hydrophobic polymers containing the polypeptide, which matricesare in the form of shaped articles, e.g., films, or microcapsule.Examples of sustained-release matrices include polyesters, hydrogels(for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acidand ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradablelactic acid-glycolic acid copolymers such as the LUPRON DEPOT™(injectable microspheres composed of lactic acid-glycolic acid copolymerand leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. Whilepolymers such as ethylene-vinyl acetate and lactic acid-glycolic acidenable release of molecules for over 100 days, certain hydrogels releaseproteins for shorter time periods. When encapsulated antibodies remainin the body for a long time, they may denature or aggregate as a resultof exposure to moisture at 37° C., resulting in a loss of biologicalactivity and possible changes in immunogenicity. Rational strategies canbe devised for stabilization depending on the mechanism involved. Forexample, if the aggregation mechanism is discovered to be intermolecularS—S bond formation through thio-disulfide interchange, stabilization maybe achieved by modifying sulfhydryl residues, lyophilizing from acidicsolutions, controlling moisture content, using appropriate additives,and developing specific polymer matrix compositions.

In some embodiments, the pharmaceutical compositions provided hereincontain therapeutically effective amounts of one or more of theantibodies provided herein, and optionally one or more additionalprophylactic of therapeutic agents, in a pharmaceutically acceptablecarrier. Such pharmaceutical compositions are useful in the prevention,treatment, or alleviation of one or more symptom of a C10orf54-mediateddisease.

Pharmaceutical carriers suitable for administration of the compoundsprovided herein include any such carriers known to those skilled in theart to be suitable for the particular mode of administration.

In addition, the antibodies provided herein may be formulated as thesole pharmaceutically active ingredient in the composition or may becombined with other active ingredients (such as one or more otherprophylactic or therapeutic agents).

The compositions can contain one or more antibodies provided herein. Inone embodiment, the antibodies are formulated into suitablepharmaceutical preparations, such as solutions, suspensions, tablets,dispersible tablets, pills, capsules, powders, sustained releaseformulations or elixirs, for oral administration or in sterile solutionsor suspensions for parenteral administration, as well as transdermalpatch preparation and dry powder inhalers. In one embodiment, theantibodies described above are formulated into pharmaceuticalcompositions using techniques and procedures well known in the art (see,e.g., Ansel (1985) Introduction to Pharmaceutical Dosage Forms, 4^(th)Ed., p. 126).

In certain embodiments of the compositions, effective concentrations ofone or more antibodies or derivatives thereof is (are) mixed with asuitable pharmaceutical carrier.

In specific embodiments, concentrations of the compounds in thecompositions are effective for delivery of an amount, uponadministration, that treats, prevents, or ameliorates aC10orf54-mediated disease or symptom thereof.

In one embodiment, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected carrier at an effective concentration such that the treatedcondition is relieved, prevented, or one or more symptoms areameliorated.

In some embodiments, the antibody provided herein is included in thepharmaceutically acceptable carrier in an effective amount sufficient toexert a therapeutically useful effect in the absence of undesirable sideeffects on the patient treated. The therapeutically effectiveconcentration can be determined empirically by testing the compounds inin vitro and in vivo systems using routine methods and then extrapolatedtherefrom for dosages for humans.

The concentration of antibody in the pharmaceutical composition willdepend on, e.g., the physicochemical characteristics of the antibody,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art.

In one embodiment, a therapeutically effective dosage produces a serumconcentration of antibody of from about 0.1 ng/ml to about 50-100 μg/ml.The pharmaceutical compositions, in another embodiment, provide a dosageof from about 0.001 mg to about 2000 mg of antibody per kilogram of bodyweight per day. Pharmaceutical dosage unit forms can be prepared toprovide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or2000 mg, and in one embodiment from about 10 mg to about 500 mg of theantibody and/or a combination of other optional essential ingredientsper dosage unit form.

The antibody can be administered at once, or may be divided into anumber of smaller doses to be administered at intervals of time. It isunderstood that the precise dosage and duration of treatment is afunction of the disease being treated and can be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuescan also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens can be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Upon mixing or addition of the antibody, the resulting mixture can be asolution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease, disorder or condition treatedand may be empirically determined.

In some embodiments, the pharmaceutical compositions are provided foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, sterile parenteralsolutions or suspensions, and oral solutions or suspensions, andoil-water emulsions containing suitable quantities of the compounds orpharmaceutically acceptable derivatives thereof. The antibody is, in oneembodiment, formulated and administered in unit-dosage forms ormultiple-dosage forms. “Unit-dose” forms as used herein refers tophysically discrete units suitable for human and animal subjects andpackaged individually as is known in the art. Each unit-dose contains apredetermined quantity of the antibody sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes and individually packaged tablets or capsules.Unit-dose forms can be administered in fractions or multiples thereof. A“multiple-dose” form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pints or gallons. Hence, multipledose form is a multiple of unit-doses which are not segregated inpackaging.

In specific embodiments, one or more anti-C10orf54 antibodies providedherein are in a liquid pharmaceutical formulation. Liquidpharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to thereby form a solution orsuspension. If desired, the pharmaceutical composition to beadministered can also contain minor amounts of nontoxic auxiliarysubstances such as wetting agents, emulsifying agents, solubilizingagents, pH buffering agents and the like, for example, acetate, sodiumcitrate, cyclodextrine derivatives, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, and other suchagents. Actual methods of preparing such dosage forms are known, or willbe apparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences (1990) Mack Publishing Co., Easton, Pa.

Dosage forms or compositions containing antibody in the range of 0.005%to 100% with the balance made up from non-toxic carrier can be prepared.Methods for preparation of these compositions are known to those skilledin the art.

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms include tablets, capsules, granules, and bulkpowders. Types of oral tablets include compressed, chewable lozenges andtablets which may be enteric-coated, sugar-coated or film-coated.Capsules can be hard or soft gelatin capsules, while granules andpowders can be provided in non-effervescent or effervescent form withthe combination of other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms. Incertain embodiments, the formulations are capsules or tablets. Thetablets, pills, capsules, troches and the like can contain one or moreof the following ingredients, or compounds of a similar nature: abinder; a lubricant; a diluent; a glidant; a disintegrating agent; acoloring agent; a sweetening agent; a flavoring agent; a wetting agent;an emetic coating; and a film coating. Examples of binders includemicrocrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, molasses, polvinylpyrrolidine, povidone,crospovidones, sucrose and starch paste. Lubricants include talc,starch, magnesium or calcium stearate, lycopodium and stearic acid.Diluents include, for example, lactose, sucrose, starch, kaolin, salt,mannitol and dicalcium phosphate. Glidants include, but are not limitedto, colloidal silicon dioxide. Disintegrating agents includecrosscarmellose sodium, sodium starch glycolate, alginic acid, cornstarch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose. Coloring agents include, for example, any of theapproved certified water soluble FD and C dyes, mixtures thereof; andwater insoluble FD and C dyes suspended on alumina hydrate. Sweeteningagents include sucrose, lactose, mannitol and artificial sweeteningagents such as saccharin, and any number of spray dried flavors.Flavoring agents include natural flavors extracted from plants such asfruits and synthetic blends of compounds which produce a pleasantsensation, such as, but not limited to peppermint and methyl salicylate.Wetting agents include propylene glycol monostearate, sorbitanmonooleate, diethylene glycol monolaurate and polyoxyethylene lauralether. Emetic-coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

The antibodies provided herein can be provided in a composition thatprotects it from the acidic environment of the stomach. For example, thecomposition can be formulated in an enteric coating that maintains itsintegrity in the stomach and releases the active compound in theintestine. The composition can also be formulated in combination with anantacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The antibody can also be mixed with other active materials which do notimpair the desired action, or with materials that supplement the desiredaction, such as antacids, H2 blockers, and diuretics. The activeingredient is an antibody or pharmaceutically acceptable derivativethereof as described herein. Higher concentrations, up to about 98% byweight of the active ingredient may be included.

In all embodiments, tablets and capsules formulations can be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

In specific embodiments, the formulations are liquid dosage forms.Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicacid, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Sweetening agents include sucrose, syrups, glycerin andartificial sweetening agents such as saccharin. Wetting agents includepropylene glycol monostearate, sorbitan monooleate, diethylene glycolmonolaurate and polyoxyethylene lauryl ether. Organic acids includecitric and tartaric acid. Sources of carbon dioxide include sodiumbicarbonate and sodium carbonate. Coloring agents include any of theapproved certified water soluble FD and C dyes, and mixtures thereof.Flavoring agents include natural flavors extracted from plants suchfruits, and synthetic blends of compounds which produce a pleasant tastesensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is, in oneembodiment, encapsulated in a gelatin capsule. Such solutions, and thepreparation and encapsulation thereof, are disclosed in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, thesolution, e.g., for example, in a polyethylene glycol, can be dilutedwith a sufficient quantity of a pharmaceutically acceptable liquidcarrier, e.g., water, to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations can be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. RE28,819 and4,358,603. Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpoly-alkylene glycol, including, but not limited to,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer tothe approximate average molecular weight of the polyethylene glycol, andone or more antioxidants, such as butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

Parenteral administration, in one embodiment, is characterized byinjection, either subcutaneously, intramuscularly or intravenously isalso contemplated herein. Injectables can be prepared in conventionalforms, either as liquid solutions or suspensions, solid forms suitablefor solution or suspension in liquid prior to injection, or asemulsions. The injectables, solutions and emulsions also contain one ormore excipients. Suitable excipients are, for example, water, saline,dextrose, glycerol or ethanol. In addition, if desired, thepharmaceutical compositions to be administered can also contain minoramounts of non-toxic auxiliary substances such as wetting or emulsifyingagents, pH buffering agents, stabilizers, solubility enhancers, andother such agents, such as for example, sodium acetate, sorbitanmonolaurate, triethanolamine oleate and cyclodextrins.

Implantation of a slow-release or sustained-release system, such that aconstant level of dosage is maintained (see, e.g., U.S. Pat. No.3,710,795) is also contemplated herein. Briefly, a compound providedherein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The antibody diffuses through the outer polymeric membrane in a releaserate controlling step. The amount of antibody contained in suchparenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Preparations for parenteral administration include sterile solutionsready for injection, sterile dry soluble products, such as lyophilizedpowders, ready to be combined with a solvent just prior to use,including hypodermic tablets, sterile suspensions ready for injection,sterile dry insoluble products ready to be combined with a vehicle justprior to use and sterile emulsions. The solutions may be either aqueousor nonaqueous. If administered intravenously, suitable carriers includephysiological saline or phosphate buffered saline (PBS), and solutionscontaining thickening and solubilizing agents, such as glucose,polyethylene glycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations can be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions includes EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles; and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations can be packaged in an ampoule, avial or a syringe with a needle. All preparations for parenteraladministration can be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.

Injectables are designed for local and systemic administration. In oneembodiment, a therapeutically effective dosage is formulated to containa concentration of at least about 0.1% w/w up to about 90% w/w or more,in certain embodiments more than 1% w/w of the active compound to thetreated tissue(s).

The antibody can be suspended in micronized or other suitable form. Theform of the resulting mixture depends upon a number of factors,including the intended mode of administration and the solubility of thecompound in the selected carrier or vehicle. The effective concentrationis sufficient for ameliorating the symptoms of the condition and may beempirically determined.

In other embodiments, the pharmaceutical formulations are lyophilizedpowders, which can be reconstituted for administration as solutions,emulsions and other mixtures. They may also be reconstituted andformulated as solids or gels.

The lyophilized powder is prepared by dissolving an antibody providedherein, or a pharmaceutically acceptable derivative thereof, in asuitable solvent. In some embodiments, the lyophilized powder issterile. The solvent may contain an excipient which improves thestability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at, inone embodiment, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. In oneembodiment, the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage or multipledosages of the compound. The lyophilized powder can be stored underappropriate conditions, such as at about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, the lyophilized powder is added to sterile water orother suitable carrier. The precise amount depends upon the selectedcompound. Such amount can be empirically determined.

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture can be a solution, suspension,emulsions or the like and can be formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The antibodies provided herein can be formulated as aerosols for topicalapplication, such as by inhalation (see, e.g., U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment of inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflations, alone or in combination with aninert carrier such as lactose. In such a case, the particles of theformulation will, in one embodiment, have diameters of less than 50microns, in one embodiment less than 10 microns.

The compounds can be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracistemal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

Other routes of administration, such as transdermal patches, includingiontophoretic and electrophoretic devices, and rectal administration,are also contemplated herein.

Transdermal patches, including iotophoretic and electrophoretic devices,are well known to those of skill in the art. For example, such patchesare disclosed in U.S. Pat. Nos. 6,267,983, 6,261,595, 6,256,533,6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433, and5,860,957.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono-, di- andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. The weight of a rectal suppository, inone embodiment, is about 2 to 3 gm.

Tablets and capsules for rectal administration can be manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

The antibodies and other compositions provided herein may also beformulated to be targeted to a particular tissue, receptor, or otherarea of the body of the subject to be treated. Many such targetingmethods are well known to those of skill in the art. All such targetingmethods are contemplated herein for use in the instant compositions. Fornon-limiting examples of targeting methods, see, e.g., U.S. Pat. Nos.6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570,6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534,5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

In one embodiment, liposomal suspensions, including tissue-targetedliposomes, such as tumor-targeted liposomes, may also be suitable aspharmaceutically acceptable carriers. These can be prepared according tomethods known to those skilled in the art. For example, liposomeformulations can be prepared as described in U.S. Pat. No. 4,522,811.Briefly, liposomes such as multilamellar vesicles (MLV's) may be formedby drying down egg phosphatidyl choline and brain phosphatidyl serine(7:3 molar ratio) on the inside of a flask. A solution of a compoundprovided herein in phosphate buffered saline lacking divalent cations(PBS) is added and the flask shaken until the lipid film is dispersed.The resulting vesicles are washed to remove unencapsulated compound,pelleted by centrifugation, and then resuspended in PBS.

Methods of Administration and Dosing

Also provided herein are compositions comprising one or more antibodiesprovided herein for use in the prevention, treatment and/or alleviationof one or more symptom of a disease, such as a C10orf54-mediateddisease.

In certain embodiments, provided herein are compositions comprising oneor more antibodies provided herein for use in the management,prevention, or treatment of a C10orf54-mediated disease and/or thealleviation of one or more symptom of a C10orf54-mediated disease.Exemplary C10orf54-mediated diseases include a cell proliferativedisorder, cancer, tumor, and graft-versus-host disease (GVHD), or asymptom thereof.

In certain embodiments, provided herein are compositions comprising oneor more antibodies provided herein for use in the prevention, treatmentand/or alleviation of one or more symptom of an C10orf54-mediateddisease, such as a cell proliferative disorder. A cell proliferativedisorder can include cancer or tumor formation, or a symptom thereof. Incertain embodiments, the cell proliferative disorder is associated withincreased expression and/or activity of C10orf54. For example, incertain embodiments, the cell proliferative disorder is associated withincreased expression of C10orf54 on the surface of a cancer cell.Examples of cell proliferative disorders to be treated, prevented, orsymptoms of which can be alleviated by the antibodies provided hereininclude, but are not limited to, bladder, breast, colon, connectivetissue, rectal, gastric, esophageal, lung, laryx, kidney, oral, ovarian,or prostate cancers, or sarcomas, melanomas, gliomas, lymphomas orleukemias, or metatases of any of these cancers. Exemplary cellproliferative disorders include, but are not limited to, a leukemia,either acute or chronic, a fibrosarcoma, and a bladder cancer.

Leukemias are cancers of the blood-forming tissues characterized bydistorted proliferation and development of leukocytes and theirprecursors in the blood and bone marrow. Leukemias are typicallyclassified as either chronic (slowly progressing) or acute (rapidlyprogressing). Leukemias can be further classified based upon the type ofblood cell affected. For example, leukemia of lymphoid cells includelymphoid leukemia, lymphocytic leukemia or lymphoblastic leukemia, andleukemia of myeloid cells include myeloid leukemia, myelogenousleukemia, myeloblastic leukemia or granulocytic leukemia. The four ofthe main types of leukemias that can be treated, prevented or symptomsthereof alleviated by the methods provided herein include acutelymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acutemyelogenous leukemia (AML) and chronic myelobastic leukemia (CML).

In one aspect, provided herein are methods for preventing or treating adisease described herein by administering to a subject a therapeuticallyeffective amount, respectively, of an anti-C10orf54 antibody describedherein, or a composition thereof. In certain embodiments, a method fortreating the disease comprises administering to subject atherapeutically effective amount of a pharmaceutical formulationcomprising an anti-C10orf54 antibody and a pharmaceutically acceptablecarrier or excipient. A method provided herein can also optionallyinclude at least one additional therapeutic agent, such as thoseprovided herein, either as a separate treatment or conjugated orrecombinately fused to an anti-C10orf54 antibody provided herein.

In one embodiment, an anti-C10orf54 antibody provided herein can be usedfor targeting C10orf54 expressed by the cancer cells by contacting theantibody with C10orf54 to form an antibody-antigen complex such that aconjugated or recombinately fused agent described herein accesses theinterior of the cell. In one embodiment, the bound antibody isinternalized into the cancer cell expressing C10orf54.

In certain embodiments, provided herein are compositions comprising oneor more antibodies provided herein for use in the prevention, treatmentand/or alleviation of one or more symptom of an C10orf54-mediateddisease, such as GVHD, or a symptom thereof. GVHD generally occursfollowing allogeneic or matched unrelated bone marrow transplants (BMT).

In some embodiments, the GVHD is acute GVHD. The symptoms of acute GVHDcan happen quickly and can be mild or severe. In certain instances,acute GVHD develops within about three months after transplant, such aswhen blood counts recover after transplant. It certain instances, theacute GVHD affects the skin, gastrointestinal (GI) tract and/or liver.For example, in some patients, acute skin GVHD begins with a rash, forexample, on the palms of the patient's hands, soles of the feet, orshoulders. However, the rash can become widespread, and may be itchy andpainful and/or might blister and peel. Acute liver GVHD may affectnormal functions of the liver, such as liver enzymes, and may in turn,cause jaundice. Acute liver GVHD may also cause the patients abdomen tobecome swollen and painful if the liver becomes enlarged. Finally,symptoms of acute gut GVHD (or GVHD of the digestive system) can includediarrhea, mucus or blood in the stool, cramping or abdominal pain,indigestion, nausea and/or loss of appetite. Other general symptoms ofacute GVHD can include anemia, low grade fever, and/or being more proneto infections. Any combination of these symptoms of acute GVHD may beprevented, treated, and/or alleviated using the compositions and methodsprovided herein.

In other embodiments, the GVHD is chronic GVHD. Chronic GVHD can occurfrom about three months to about a year or longer after transplant.Chronic GVHD can be mild or severe, and generally includes symptomssimilar to those of acute GVHD. Chronic GVHD can affect the skin anddigestive system, including the liver but can also involve other organsand the immune system (e.g., making the patient more prone toinfections) and/or connective tissues. Symptoms of chronic skin GVHDinclude a rash, dry skin, tight skin, itchy skin, darkening of the colorof the skin, thickening of the skin, and/or may affect hair (e.g., hairloss, turning gray) or nails (e.g., hard or brittle nails). Chronic gutGVHD can affect the digestive system, mouth, esophagus, lining of thestomach, and/or lining of the bowel, and symptoms can include diarrhea,dry or sore mouth, painful swallowing, low nutrient absorption by thestomach, bloating, stomach cramps. Chronic liver GVHD can cause damageand scarring of the liver (cirrhosis). Chronic GVHD of the eyes canaffect the glands that make tears, causing eyes to become dry, burningand painful or difficult to tolerate bright light. Chronic lung GVHD cancause shortness of breath, wheezing, persistent cough, and/or being moreprone to chest infections. Chronic GVHD affects tendons (e.g.,inflammation) that connect muscle to bone causing difficultystraightening or bending your arms and legs. Any combination of thesesymptoms of chronic GVHD may be prevented, treated, and/or alleviatedusing the compositions and methods provided herein.

In certain embodiments, an antibody provided herein may be used in, forexample, in vitro, ex vivo, and in vivo therapeutic methods. In someembodiments, provided herein are methods for inhibiting cell growth orproliferation, either in vivo or in vitro, the method comprisingcontacting a cell with an effective amount of a composition or ananti-C10orf54 antibody provided herein. In some embodiments, an antibodyprovided herein may be used in a method for inducing cell death. Themethod can comprise contacting a cell with an effective amount of acomposition or an anti-C10orf54 antibody provided herein. The methodscan be performed under conditions permissive for binding of the antibodyto a C10orf54 polypeptide, polypeptide fragment or epitope, such as, butnot limited to when the C10orf54 polypeptide is expressed on the surfaceof a cell. For inhibiting the cell growth or proliferation of a cell,the inhibition can include decreasing a cell's growth or proliferationby at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%,and can include cell death. In certain embodiments, the cell is a cancercell or a pre-cancerous cell. In certain embodiments, the cell is abladder, breast, colon, connective tissue, rectal, gastric, esophageal,lung, laryx, kidney, oral, ovarian, or prostate cancer cell, or asarcoma, melanoma, glioma, lymphoma or leukemia cell. In certainembodiments, the cell is an immune cell expressing a C10orf54polypeptide, such as, but not limited to, a regulatory T cell (i.e. asuppressor T cell).

An anti-C10orf54 antibody can be administered to a human for therapeuticor prophylactic purposes. Moreover, an anti-C10orf54 antibody can beadministered to a non-human mammal expressing C10orf54 with which theantibody cross-reacts (e.g., a primate, pig, rat, or mouse) forveterinary purposes or as an animal model of human disease. Regardingthe latter, such animal models may be useful for evaluating thetherapeutic or prophylactic efficacy of antibodies or immunoconjugatesprovided herein (e.g., testing of dosages and time courses ofadministration).

In certain embodiments, an antibody provided herein can be used in amethod of modulating an immune response in a subject. Such methods caninclude administering an effective amount of the composition ofcomprising an antibody provided herein to a subject. In some aspects,the modulating can include (a) increasing T cell activation; (b)increasing T cell proliferation; and/or (c) increasing cytokineproduction. Methods for assaying the modulation of an immune responseare well known to one of skill in the art, and it is understood that askill artisian would be able to readily conduct such assays.

In a specific embodiment, a composition for use in the management,prevention, treatment and/or alleviation of one or more symptom of aC10orf54-mediated disease comprises an antibody as described herein. Inanother specific embodiment, a composition for use in the management,prevention, treatment and/or alleviation of one or more symptom of aC10orf54-mediated disease comprises an antigen-binding fragment, afusion protein or an functional fragment of an antibody as describedherein.

In another embodiment, a composition for use in the management,prevention, treatment and/or alleviation of one or more symptom of aC10orf54-mediated disease comprises one or more antibodies describedherein.

As discussed in more detail elsewhere herein, a composition providedherein may be used either alone or in combination with other compoundsor compositions. Moreover, the antibodies may further be recombinantlyfused to a heterologous polypeptide at the N- or C-terminus orchemically conjugated (including covalently and non-covalentlyconjugations) to polypeptides or other compositions. For example,antibodies provided herein may be recombinantly fused or conjugated tomolecules useful as labels in detection assays and effector moleculessuch as heterologous polypeptides, drugs, radionucleotides, or toxins.See, e.g., PCT publications WO 92/08495; WO 91/14438; WO 89/12624; U.S.Pat. No. 5,314,995; and EP 396,387.

Antibodies provided herein may be used, for example, to purify, detect,and target C10orf54 antigens, in both in vitro and in vivo diagnosticand therapeutic methods. For example, the modified antibodies have usein immunoassays for qualitatively and quantitatively measuring levels ofC10orf54 in biological samples. See, e.g., Harlow et al., Antibodies: ALaboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988)(incorporated by reference herein in its entirety).

Also provided herein are methods of managing, treating, preventingand/or ameliorating one or more symptom of a C10orf54-mediated diseaseby administrating to a subject of an effective amount of an antibody, orpharmaceutical composition comprising an antibody provided herein. Inone aspect, an antibody is substantially purified (e.g., substantiallyfree from substances that limit its effect or produce undesiredside-effects). In specific embodiments, the antibody is a humanizedmonoclonal antibody. The subject administered a therapy can be a mammalsuch as non-primate (e.g., cows, pigs, horses, cats, dogs, rats etc.) ora primate (e.g., a monkey, such as a cynomolgous monkey, or a human). Ina specific embodiment, the subject is a human. In another embodiment,the subject is a human with a C10orf54-mediated disease.

Various delivery systems are known and can be used to administer aprophylactic or therapeutic agent (e.g., an antibody provided herein),including, but not limited to, encapsulation in liposomes,microparticles, microcapsules, recombinant cells capable of expressingthe antibody, receptor-mediated endocytosis (see, e.g., Wu and Wu, J.Biol. Chem. 262:4429-4432 (1987)), construction of a nucleic acid aspart of a retroviral or other vector, etc. Methods of administering aprophylactic or therapeutic agent (e.g., an antibody provided herein),or pharmaceutical composition include, but are not limited to,parenteral administration (e.g., intradermal, intramuscular,intraperitoneal, intravenous and subcutaneous), epidural, and mucosal(e.g., intranasal and oral routes). In a specific embodiment, aprophylactic or therapeutic agent (e.g., an antibody provided herein),or a pharmaceutical composition is administered intranasally,intramuscularly, intravenously, or subcutaneously. The prophylactic ortherapeutic agents, or compositions may be administered by anyconvenient route, for example by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, intranasal mucosa, rectal and intestinal mucosa, etc.) and maybe administered together with other biologically active agents.Administration can be systemic or local. In addition, pulmonaryadministration can also be employed, e.g., by use of an inhaler ornebulizer, and formulation with an aerosolizing agent. See, e.g., U.S.Pat. Nos. 6,019,968, 5,985,320, 5,985,309, 5,934,272, 5,874,064,5,855,913, 5,290,540, and 4,880,078; and PCT Publication Nos. WO92/19244, WO 97/32572, WO 97/44013, WO 98/31346, and WO 99/66903, eachof which is incorporated herein by reference their entirety.

In a specific embodiment, it may be desirable to administer aprophylactic or therapeutic agent, or a pharmaceutical compositionprovided herein locally to the area in need of treatment. This may beachieved by, for example, and not by way of limitation, local infusion,by topical administration (e.g., by intranasal spray), by injection, orby means of an implant, the implant being of a porous, non-porous, orgelatinous material, including membranes, such as sialastic membranes,or fibers. In certain embodiments, when administering an antibodyprovided herein, care must be taken to use materials to which theantibody does not absorb.

In another embodiment, a therapeutic agent or composition providedherein can be delivered in a vesicle, in particular a liposome (seeLanger, 1990, Science 249:1527-1533; Treat et al., in Liposomes in theTherapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler(eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp.317-327; see generally ibid.).

In another embodiment, a therapeutic agent or composition providedherein can be delivered in a controlled release or sustained releasesystem. In one embodiment, a pump may be used to achieve controlled orsustained release (see Langer, supra; Sefton, 1987, CRC Crit. Ref.Biomed. Eng. 14:20; Buchwald et al., 1980, Surgery 88:507; Saudek etal., 1989, N. Engl. J. Med. 321:574). In another embodiment, polymericmaterials can be used to achieve controlled or sustained release of atherapeutic agent (e.g., an antibody provided herein) or a compositionprovided herein (see e.g., Medical Applications of Controlled Release,Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); ControlledDrug Bioavailability, Drug Product Design and Performance, Smolen andBall (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J.,Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985,Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard etal., 1989, J. Neurosurg. 7 1:105); U.S. Pat. Nos. 5,679,377; 5,916,597;5,912,015; 5,989,463; 5,128,326; PCT Publication No. WO 99/15154; andPCT Publication No. WO 99/20253.

Examples of polymers used in sustained release formulations include, butare not limited to, poly(2-hydroxy ethyl methacrylate), poly(methylmethacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate),poly(methacrylic acid), polyglycolides (PLG), polyanhydrides,poly(N-vinyl pyrrolidone), poly(vinyl alcohol), polyacrylamide,poly(ethylene glycol), polylactides (PLA), poly(lactide-co-glycolides)(PLGA), and polyorthoesters. In a specific embodiment, the polymer usedin a sustained release formulation is inert, free of leachableimpurities, stable on storage, sterile, and biodegradable. In yetanother embodiment, a controlled or sustained release system can beplaced in proximity of the therapeutic target, e.g., the nasal passagesor lungs, thus requiring only a fraction of the systemic dose (see,e.g., Goodson, in Medical Applications of Controlled Release, supra,vol. 2, pp. 115-138 (1984)). Controlled release systems are discussed inthe review by Langer (1990, Science 249:1527-1533). Any technique knownto one of skill in the art can be used to produce sustained releaseformulations comprising one or more antibodies provided herein. See,e.g., U.S. Pat. No. 4,526,938, PCT publication WO 91/05548, PCTpublication WO 96/20698, Ning et al., 1996, “IntratumoralRadioimmunotherapy of a Human Colon Cancer Xenograft Using aSustained-Release Gel,” Radiotherapy & Oncology 39:179-189, Song et al.,1995, “Antibody Mediated Lung Targeting of Long-Circulating Emulsions,”PDA Journal of Pharmaceutical Science & Technology 50:372-397, Cleek etal., 1997, “Biodegradable Polymeric Carriers for a bFGF Antibody forCardiovascular Application,” Pro. Int'l. Symp. Control. Rel. Bioact.Mater. 24:853-854, and Lam et al., 1997, “Microencapsulation ofRecombinant Humanized Monoclonal Antibody for Local Delivery,” Proc.Int'l. Symp. Control Rel. Bioact. Mater. 24:759-760.

In a specific embodiment, where the composition provided herein is anucleic acid encoding a prophylactic or therapeutic agent (e.g., anantibody provided herein), the nucleic acid can be administered in vivoto promote expression of its encoded therapeutic agent, by constructingit as part of an appropriate nucleic acid expression vector andadministering it so that it becomes intracellular, e.g., by use of aretroviral vector (see U.S. Pat. No. 4,980,286), or by direct injection,or by use of microparticle bombardment (e.g., a gene gun; Biolistic,Dupont), or coating with lipids or cell surface receptors ortransfecting agents, or by administering it in linkage to ahomeobox-like peptide which is known to enter the nucleus (see, e.g.,Joliot et al., 1991, Proc. Natl. Acad. Sci. USA 88:1864-1868), etc.Alternatively, a nucleic acid can be introduced intracellularly andincorporated within host cell DNA for expression by homologousrecombination.

In a specific embodiment, a composition comprises one, two or moreantibodies provided herein. In another embodiment, a compositioncomprises one, two or more antibodies provided herein and a prophylacticor therapeutic agent other than an antibody provided herein. In certainembodiments, the agents are known to be useful for or have been or arecurrently used for the prevention, treatment and/or alleviation of oneor more symptom of a C10orf54-mediated disease. In addition toprophylactic or therapeutic agents, the compositions provided herein mayalso comprise a carrier.

The compositions provided herein include bulk drug compositions usefulin the manufacture of pharmaceutical compositions (e.g., compositionsthat are suitable for administration to a subject or patient) that canbe used in the preparation of unit dosage forms. In a specificembodiment, a composition provided herein is a pharmaceuticalcomposition. Such compositions comprise a prophylactically ortherapeutically effective amount of one or more prophylactic ortherapeutic agents (e.g., an antibody provided herein or otherprophylactic or therapeutic agent), and a pharmaceutically acceptablecarrier. In certain embodiments, the pharmaceutical compositions areformulated to be suitable for the route of administration to a subject.

In a specific embodiment, the composition is formulated in accordancewith routine procedures as a pharmaceutical composition adapted forintravenous administration to human beings. Typically, compositions forintravenous administration are solutions in sterile isotonic aqueousbuffer. Where necessary, the composition may also include a solubilizingagent and a local anesthetic such as lignocamne to ease pain at the siteof the injection. Such compositions, however, may be administered by aroute other than intravenous.

Generally, the ingredients of compositions provided herein are suppliedeither separately or mixed together in unit dosage form, for example, asa dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette indicating the quantityof active agent. Where the composition is to be administered byinfusion, it can be dispensed with an infusion bottle containing sterilepharmaceutical grade water or saline. Where the composition isadministered by injection, an ampoule of sterile water for injection orsaline can be provided so that the ingredients may be mixed prior toadministration.

In certain embodiments, an antibody provided herein is packaged in ahermetically sealed container such as an ampoule or sachette indicatingthe quantity of antibody. In one embodiment, the antibody is supplied asa dry sterilized lyophilized powder or water free concentrate in ahermetically sealed container and can be reconstituted, e.g., with wateror saline to the appropriate concentration for administration to asubject. In certain embodiments, the antibody is supplied as a drysterile lyophilized powder in a hermetically sealed container at a unitdosage of at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 2mg, or at least 3 mg, such as at least 5 mg, at least 10 mg, at least 15mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 45 mg, atleast 50 mg, at least 60 mg, at least 75 mg, at least 80 mg, at least 85mg, at least 90 mg, at least 95 mg, or at least 100 mg. The lyophilizedantibody can be stored at between 2 and 8° C. in its original containerand the antibody can be administered within 12 hours, such as within 6hours, within 5 hours, within 3 hours, or within 1 hour after beingreconstituted. In an alternative embodiment, an antibody is supplied inliquid form in a hermetically sealed container indicating the quantityand concentration of the antibody. In certain embodiments, the liquidform of the antibody is supplied in a hermetically sealed container atleast 0.1 mg/ml, at least 0.5 mg/ml, or at least 1 mg/ml, such as atleast 5 mg/ml, at least 10 mg/ml, at least 15 mg/ml, at least 25 mg/ml,at least 30 mg/ml, at least 40 mg/ml, at least 50 mg/ml, at least 60mg/ml, at least 70 mg/ml, at least 80 mg/ml, at least 90 mg/ml, or atleast 100 mg/ml.

The compositions provided herein can be formulated as neutral or saltforms. Pharmaceutically acceptable salts include those formed withanions such as those derived from hydrochloric, phosphoric, acetic,oxalic, tartaric acids, etc., and those formed with cations such asthose derived from sodium, potassium, ammonium, calcium, ferrichydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol,histidine, procaine, etc.

The amount of a therapeutic agent (e.g., an antibody provided herein) ora composition provided herein that will be effective in the prevention,treatment and/or alleviation of one or more symptom of aC10orf54-mediated disease can be determined by standard clinicaltechniques.

Accordingly, a dosage of an antibody or a composition that results in aserum titer of from about 0.1 μg/ml to about 450 μg/ml, and in someembodiments at least 0.1 μg/ml, at least 0.2 μg/ml, at least 0.4 μg/ml,at least 0.5 μg/ml, at least 0.6 μg/ml, at least 0.8 μg/ml, at least 1μg/ml, at least 1.5 μg/ml, such as at least 2 μg/ml, at least 5 μg/ml,at least 10 μg/ml, at least 15 μg/ml, at least 20 μg/ml, at least 25μg/ml, at least μg/ml, at least 35 μg/ml, at least 40 μg/ml, at least 50μg/ml, at least 75 μg/ml, at least 100 μg/ml, at least 125 μg/ml, atleast 150 μg/ml, at least 200 μg/ml, at least 250 μg/ml, at least 300μg/ml, at least 350 μg/ml, at least 400 μg/ml, or at least 450 μg/ml canbe administered to a human for the prevention, treatment and/oralleviation of one or more symptom of a C10orf54-mediated disease. Inaddition, in vitro assays may optionally be employed to help identifyoptimal dosage ranges. The precise dose to be employed in theformulation will also depend on the route of administration, and theseriousness of a C10orf54-mediated disease, and should be decidedaccording to the judgment of the practitioner and each patientscircumstances.

Effective doses may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For the antibodies provided herein, the dosage administered to a patientcan be, in certain embodiments, 0.1 mg/kg to 100 mg/kg of the patientsbody weight. In some embodiments, the dosage administered to the patientis about 1 mg/kg to about 75 mg/kg of the patients body weight. Incertain embodiments, the dosage administered to a patient is between 1mg/kg and 20 mg/kg of the patients body weight, such as 1 mg/kg to 5mg/kg of the patients body weight. Generally, human antibodies have alonger half-life within the human body than antibodies from otherspecies due to the immune response to the foreign polypeptides. Thus,lower dosages of human antibodies and less frequent administration isoften possible. Further, the dosage and frequency of administration ofthe antibodies provided herein may be reduced by enhancing uptake andtissue penetration of the antibodies by modifications such as, forexample, lipidation.

In one embodiment, approximately 100 mg/kg or less, approximately 75mg/kg or less, approximately 50 mg/kg or less, approximately 25 mg/kg orless, approximately 10 mg/kg or less, approximately 5 mg/kg or less,approximately 1 mg/kg or less, approximately 0.5 mg/kg or less, orapproximately 0.1 mg/kg or less of an antibody provided herein isadministered 5 times, 4 times, 3 times, 2 times or 1 time to prevent,treat or alleviate one or more symptom of a C10orf54-mediated disease.In some embodiments, an antibody provided herein is administered about1-12 times, wherein the doses may be administered as necessary, e.g.,weekly, biweekly, monthly, bimonthly, trimonthly, etc., as determined bya physician. In some embodiments, a lower dose (e.g., 1-15 mg/kg) can beadministered more frequently (e.g., 3-6 times). In other embodiments, ahigher dose (e.g., 25-100 mg/kg) can be administered less frequently(e.g., 1-3 times). However, as will be apparent to those in the art,other dosing amounts and schedules are easily determinable and withinthe scope of the invention.

In a specific embodiment, approximately 100 mg/kg, approximately 75mg/kg or less, approximately 50 mg/kg or less, approximately 25 mg/kg orless, approximately 10 mg/kg or less, approximately 5 mg/kg or less,approximately 1 mg/kg or less, approximately 0.5 mg/kg or less,approximately 0.1 mg/kg or less of an antibody provided herein in asustained release formulation is administered to a subject, such as ahuman, to prevent, treat and/or alleviate one or more symptom of aC10orf54-mediated disease. In another specific embodiment, anapproximately 100 mg/kg, approximately 75 mg/kg or less, approximately50 mg/kg or less, approximately 25 mg/kg or less, approximately 10 mg/kgor less, approximately 5 mg/kg or less, approximately 1 mg/kg or less,approximately 0.5 mg/kg or less, or approximately 0.1 mg/kg or lessbolus of an antibody provided herein not in a sustained releaseformulation is administered to a subject, such as a human, to prevent,treat and/or alleviate one or more symptom of a C10orf54-mediateddisease, and after a certain period of time, approximately 100 mg/kg,approximately 75 mg/kg or less, approximately 50 mg/kg or less,approximately 25 mg/kg or less, approximately 10 mg/kg or less,approximately 5 mg/kg or less, approximately 1 mg/kg or less,approximately 0.5 mg/kg or less, or approximately 5 mg/kg or less of anantibody provided herein in a sustained release is administered to thesubject (e.g., intranasally or intramuscularly) one, two, three or fourtimes. In accordance with this embodiment, a certain period of time canbe 1 to 5 days, a week, two weeks, or a month.

In some embodiments, a single dose of an antibody provided herein isadministered to a patient to prevent, treat and/or alleviate one or moresymptom of a C10orf54-mediated disease two, three, four, five, six,seven, eight, nine, ten, eleven, twelve times, thirteen, fourteen,fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one,twenty-two, twenty-three, twenty-four, twenty five, or twenty six atbiweekly (e.g., about 14 day) intervals over the course of a year,wherein the dose is selected from the group consisting of about 0.1mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg,about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg,about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg,or a combination thereof (e.g., each dose monthly dose may or may not beidentical).

In another embodiment, a single dose of an antibody provided herein isadministered to patient to prevent, treat and/or alleviate one or moresymptom of a C10orf54-mediated disease two, three, four, five, six,seven, eight, nine, ten, eleven, or twelve times at about monthly (e.g.,about 30 day) intervals over the course of a year, wherein the dose isselected from the group consisting of about 0.1 mg/kg, about 0.5 mg/kg,about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg,about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg,about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, or a combinationthereof (e.g., each dose monthly dose may or may not be identical).

In one embodiment, a single dose of an antibody provided herein isadministered to a patient to treat, prevent and/or alleviate a symptomof a C10orf54-mediated disease two, three, four, five, or six times atabout bi-monthly (e.g., about 60 day) intervals over the course of ayear, wherein the dose is selected from the group consisting of about0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg,about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg,about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about100 mg/kg, or a combination thereof (e.g., each bi-monthly dose may ormay not be identical).

In some embodiments, a single dose of an antibody provided herein isadministered to a patient to treat, prevent and/or alleviate one or moresymptom of a C10orf54-mediated disease two, three, or four times atabout tri-monthly (e.g., about 120 day) intervals over the course of ayear, wherein the dose is selected from the group consisting of about0.1 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 5 mg/kg, about 10mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg,about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg,about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about100 mg/kg, or a combination thereof (e.g., each tri-monthly dose may ormay not be identical).

In certain embodiments, the route of administration for a dose of anantibody provided herein to a patient is intranasal, intramuscular,intravenous, or a combination thereof, but other routes described hereinare also acceptable. Each dose may or may not be administered by anidentical route of administration. In some embodiments, an antibodyprovided herein may be administered via multiple routes ofadministration simultaneously or subsequently to other doses of the sameor a different antibody provided herein.

In certain embodiments, antibodies provided herein are administeredprophylactically or therapeutically to a subject. Antibodies can beprophylactically or therapeutically administered to a subject so as toprevent, lessen or alleviate a C10orf54-mediated disease or symptomthereof.

Diagnostic Use of Antibodies

Labeled antibodies provided herein and derivatives and analogs thereof,which bind to a C10orf54 antigen can be used for diagnostic purposes todetect, diagnose, or monitor a C10orf54-mediated disease. Also providedherein are methods for the detection of a C10orf54-mediated diseasecomprising: (a) assaying the expression of a C10orf54 antigen in cellsor a tissue sample of a subject using one or more antibodies providedherein that bind to the C10orf54 antigen; and (b) comparing the level ofthe C10orf54 antigen with a control level, e.g., levels in normal tissuesamples (e.g., from a patient not having a C10orf54-mediated disease, orfrom the same patient before disease onset), whereby an increase in theassayed level of C10orf54 antigen compared to the control level of theC10orf54 antigen is indicative of a C10orf54-mediated disease.

Also provided herein is a diagnostic assay for diagnosing aC10orf54-mediated disease comprising: (a) assaying for the level of aC10orf54 antigen in cells or a tissue sample of an individual using oneor more antibodies provided herein that bind to a C10orf54 antigen; and(b) comparing the level of the C10orf54 antigen with a control level,e.g., levels in normal tissue samples, whereby an increase in theassayed C10orf54 antigen level compared to the control level of theC10orf54 antigen is indicative of a C10orf54-mediated disease. A moredefinitive diagnosis of a C10orf54-mediated disease may allow healthprofessionals to employ preventative measures or aggressive treatmentearlier thereby preventing the development or further progression of theC10orf54-mediated disease.

Antibodies provided herein can be used to assay C10orf54 antigen levelsin a biological sample using classical immunohistological methods asdescribed herein or as known to those of skill in the art (e.g., seeJalkanen et al., 1985, J. Cell. Biol. 101:976-985; and Jalkanen et al.,1987, J. Cell. Biol. 105:3087-3096). Other antibody-based methods usefulfor detecting protein gene expression include immunoassays, such as theenzyme linked immunosorbent assay (ELISA) and the radioimmunoassay(RIA). Suitable antibody assay labels are known in the art and includeenzyme labels, such as, glucose oxidase; radioisotopes, such as iodine(¹²⁵I, ¹²¹I), carbon (¹⁴C), sulfur (³⁵S), tritium (³H), indium (¹²¹In),and technetium (⁹⁹Tc); luminescent labels, such as luminol; andfluorescent labels, such as fluorescein and rhodamine, and biotin.

One aspect provided herein is the detection and diagnosis of aC10orf54-mediated disease in a human. In one embodiment, diagnosiscomprises: a) administering (for example, parenterally, subcutaneously,or intraperitoneally) to a subject an effective amount of a labeledantibody that binds to a C10orf54 antigen; b) waiting for a timeinterval following the administering for permitting the labeled antibodyto preferentially concentrate at sites in the subject where the C1 orf54antigen is expressed (and for unbound labeled molecule to be cleared tobackground level); c) determining background level; and d) detecting thelabeled antibody in the subject, such that detection of labeled antibodyabove the background level indicates that the subject has aC10orf54-mediated disease. Background level can be determined by variousmethods including, comparing the amount of labeled molecule detected toa standard value previously determined for a particular system.

It will be understood in the art that the size of the subject and theimaging system used will determine the quantity of imaging moiety neededto produce diagnostic images. In the case of a radioisotope moiety, fora human subject, the quantity of radioactivity injected will normallyrange from about 5 to 20 millicuries of ⁹⁹Tc. The labeled antibody willthen preferentially accumulate at the location of cells which containthe specific protein. In vivo tumor imaging is described in S. W.Burchiel et al., “Immunopharmacokinetics of Radiolabeled Antibodies andTheir Fragments.” (Chapter 13 in Tumor Imaging: The RadiochemicalDetection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., MassonPublishing Inc. (1982).

Depending on several variables, including the type of label used and themode of administration, the time interval following the administrationfor permitting the labeled antibody to preferentially concentrate atsites in the subject and for unbound labeled antibody to be cleared tobackground level is 6 to 48 hours or 6 to 24 hours or 6 to 12 hours. Inanother embodiment the time interval following administration is 5 to 20days or 5 to 10 days.

In one embodiment, monitoring of a C10orf54-mediated disease is carriedout by repeating the method for diagnosing the a C10orf54-mediateddisease, for example, one month after initial diagnosis, six monthsafter initial diagnosis, one year after initial diagnosis, etc.

Presence of the labeled molecule can be detected in the subject usingmethods known in the art for in vivo scanning. These methods depend uponthe type of label used. Skilled artisans will be able to determine theappropriate method for detecting a particular label. Methods and devicesthat may be used in the diagnostic methods provided herein include, butare not limited to, computed tomography (CT), whole body scan such asposition emission tomography (PET), magnetic resonance imaging (MRI),and sonography.

In a specific embodiment, the molecule is labeled with a radioisotopeand is detected in the patient using a radiation responsive surgicalinstrument (Thurston et al., U.S. Pat. No. 5,441,050). In anotherembodiment, the molecule is labeled with a fluorescent compound and isdetected in the patient using a fluorescence responsive scanninginstrument. In another embodiment, the molecule is labeled with apositron emitting metal and is detected in the patient using positronemission-tomography. In yet another embodiment, the molecule is labeledwith a paramagnetic label and is detected in a patient using magneticresonance imaging (MRI).

Methods of Producing Antibodies

Antibodies provided herein that bind to an antigen can be produced byany method known in the art for the synthesis of antibodies, inparticular, by chemical synthesis or by recombinant expressiontechniques. The practice of the invention employs, unless otherwiseindicated, conventional techniques in molecular biology, microbiology,genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR,oligonucleotide synthesis and modification, nucleic acid hybridization,and related fields within the skill of the art. These techniques aredescribed in the references cited herein and are fully explained in theliterature. See, e.g., Maniatis et al. (1982) Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press; Sambrook et al.(1989), Molecular Cloning: A Laboratory Manual, Second Edition, ColdSpring Harbor Laboratory Press; Sambrook et al. (2001) MolecularCloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.; Ausubel et al., Current Protocols in MolecularBiology, John Wiley & Sons (1987 and annual updates); Current Protocolsin Immunology, John Wiley & Sons (1987 and annual updates) Gait (ed.)(1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press;Eckstein (ed.) (1991) Oligonucleotides and Analogues: A PracticalApproach, IRL Press; Birren et al. (eds.) (1999) Genome Analysis: ALaboratory Manual, Cold Spring Harbor Laboratory Press.

Polyclonal antibodies that bind to an antigen can be produced by variousprocedures well-known in the art. For example, a human antigen can beadministered to various host animals including, but not limited to,rabbits, mice, rats, etc. to induce the production of sera containingpolyclonal antibodies specific for the human antigen. Various adjuvantsmay be used to increase the immunological response, depending on thehost species, and include but are not limited to, Freund's (complete andincomplete), mineral gels such as aluminum hydroxide, surface activesubstances such as lysolecithin, pluronic polyols, polyanions, peptides,oil emulsions, keyhole limpet hemocyanins, dinitrophenol, andpotentially useful human adjuvants such as BCG (bacille Calmette-Guerin)and Corynebacterium parvum. Such adjuvants are also well known in theart.

Monoclonal antibodies can be prepared using a wide variety of techniquesknown in the art including the use of hybridoma, recombinant, and phagedisplay technologies, or a combination thereof. For example, monoclonalantibodies can be produced using hybridoma techniques including thoseknown in the art and taught, for example, in Harlow et al., Antibodies:A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed.1988); Hammerling et al., in: Monoclonal Antibodies and T-CellHybridomas 563 681 (Elsevier, N.Y., 1981) (the references incorporatedby reference in their entireties). The term “monoclonal antibody” asused herein is not limited to antibodies produced through hybridomatechnology. Other exemplary methods of producing monoclonal antibodiesare discussed elsewhere herein, such as e.g., use of the KM Mouse™.Additional exemplary methods of producing monoclonal antibodies areprovided in the Examples herein.

Methods for producing and screening for specific antibodies usinghybridoma technology are routine and well known in the art. Briefly,mice can be immunized with a C10orf54 antigen and once an immuneresponse is detected, e.g., antibodies specific for C10orf54 antigen aredetected in the mouse serum, the mouse spleen is harvested andsplenocytes isolated. The splenocytes are then fused by well knowntechniques to any suitable myeloma cells, for example cells from cellline SP20 available from the ATCC. Hybridomas are selected and cloned bylimited dilution.

Additionally, a RIMMS (repetitive immunization multiple sites) techniquecan be used to immunize an animal (Kilptrack et al., 1997 Hybridoma16:381-9, incorporated by reference in its entirety). The hybridomaclones are then assayed by methods known in the art for cells thatsecrete antibodies capable of binding a given polypeptide. Ascitesfluid, which generally contains high levels of antibodies, can begenerated by immunizing mice with positive hybridoma clones.

Accordingly, also provided herein are methods of generating antibodiesby culturing a hybridoma cell secreting a modified antibody providedherein wherein, in certain embodiments, the hybridoma is generated byfusing splenocytes isolated from a mouse immunized with a C10orf54antigen with myeloma cells and then screening the hybridomas resultingfrom the fusion for hybridoma clones that secrete an antibody able tobind to a C10orf54 antigen.

Antibody fragments which recognize specific C10orf54 antigens may begenerated by any technique known to those of skill in the art. Forexample, Fab and F(ab′)₂ fragments provided herein may be produced byproteolytic cleavage of immunoglobulin molecules, using enzymes such aspapain (to produce Fab fragments) or pepsin (to produce F(ab′)₂fragments). F(ab′)₂ fragments contain the variable region, the lightchain constant region and the CH₁ domain of the heavy chain. Further,the antibodies provided herein can also be generated using various phagedisplay methods known in the art.

For example, antibodies can also be generated using various phagedisplay methods. In phage display methods, functional antibody domainsare displayed on the surface of phage particles which carry thepolynucleotide sequences encoding them. In particular, DNA sequencesencoding VH and VL domains are amplified from animal cDNA libraries(e.g., human or murine cDNA libraries of affected tissues). The DNAencoding the VH and VL domains are recombined together with an scFvlinker by PCR and cloned into a phagemid vector. The vector iselectroporated in E. coli and the E. coli is infected with helper phage.Phage used in these methods are typically filamentous phage including fdand M13 and the VH and VL domains are usually recombinantly fused toeither the phage gene III or gene VIII. Phage expressing an antigenbinding domain that binds to a particular antigen can be selected oridentified with antigen, e.g., using labeled antigen or antigen bound orcaptured to a solid surface or bead. Examples of phage display methodsthat can be used to make the antibodies provided herein include thosedisclosed in Brinkman et al., 1995, J. Immunol. Methods 182:41-50; Ameset al., 1995, J. Immunol. Methods 184:177-186; Kettleborough et al.,1994, Eur. J. Immunol. 24:952-958; Persic et al., 1997, Gene 187:9-18;Burton et al., 1994, Advances in Immunology 57:191-280; PCT ApplicationNo. PCT/GB91/O1 134; International Publication Nos. WO 90/02809, WO91/10737, WO 92/01047, WO 92/18619, WO 93/1 1236, WO 95/15982, WO95/20401, and WO97/13844; and U.S. Pat. Nos. 5,698,426, 5,223,409,5,403,484, 5,580,717, 5,427,908, 5,750,753, 5,821,047, 5,571,698,5,427,908, 5,516,637, 5,780,225, 5,658,727, 5,733,743 and 5,969,108;each of which is incorporated herein by reference in its entirety.

As described in the above references, after phage selection, theantibody coding regions from the phage can be isolated and used togenerate whole antibodies, including human antibodies, or any otherdesired antigen binding fragment, and expressed in any desired host,including mammalian cells, insect cells, plant cells, yeast, andbacteria, e.g., as described below. Techniques to recombinantly produceFab, Fab′ and F(ab′)₂ fragments can also be employed using methods knownin the art such as those disclosed in PCT publication No. WO 92/22324;Mullinax et al., 1992, BioTechniques 12(6):864-869; Sawai et al., 1995,AJRI 34:26-34; and Better et al., 1988, Science 240:1041-1043 (thereferences incorporated by reference in their entireties).

To generate whole antibodies, PCR primers including VH or VL nucleotidesequences, a restriction site, and a flanking sequence to protect therestriction site can be used to amplify the VH or VL sequences in scFvclones. Utilizing cloning techniques known to those of skill in the art,the PCR amplified VH domains can be cloned into vectors expressing a VHconstant region, e.g., the human gamma 4 constant region, and the PCRamplified VL domains can be cloned into vectors expressing a VL constantregion, e.g., human kappa or lambda constant regions. The VH and VLdomains may also cloned into one vector expressing the necessaryconstant regions. The heavy chain conversion vectors and light chainconversion vectors are then co-transfected into cell lines to generatestable or transient cell lines that express full-length antibodies,e.g., IgG, using techniques known to those of skill in the art.

For some uses, including in vivo use of antibodies in humans and invitro detection assays, human or chimeric antibodies can be used.Completely human antibodies are particularly desirable for therapeutictreatment of human subjects. Human antibodies can be made by a varietyof methods known in the art including phage display methods describedabove using antibody libraries derived from human immunoglobulinsequences. See also U.S. Pat. Nos. 4,444,887 and 4,716,111; andInternational Publication Nos. WO 98/46645, WO 98/50433, WO 98/24893, WO98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; each of which isincorporated herein by reference in its entirety.

In specific embodiments, human antibodies are produced. Human antibodiesand/or fully human antibodies can be produced using any method known inthe art, including the Examples provided herein. For example, transgenicmice which are incapable of expressing functional endogenousimmunoglobulins, but which can express human immunoglobulin genes. Forexample, the human heavy and light chain immunoglobulin gene complexesmay be introduced randomly or by homologous recombination into mouseembryonic stem cells. Alternatively, the human variable region, constantregion, and diversity region may be introduced into mouse embryonic stemcells in addition to the human heavy and light chain genes. The mouseheavy and light chain immunoglobulin genes may be rendered nonfunctional separately or simultaneously with the introduction of humanimmunoglobulin loci by homologous recombination. In particular,homozygous deletion of the J_(H) region prevents endogenous antibodyproduction. The modified embryonic stem cells are expanded andmicroinjected into blastocysts to produce chimeric mice. The chimericmice are then bred to produce homozygous offspring which express humanantibodies. The transgenic mice are immunized in the normal fashion witha selected antigen, e.g., all or a portion of the polypeptide.Monoclonal antibodies directed against the antigen can be obtained fromthe immunized, transgenic mice using conventional hybridoma technology.The human immunoglobulin transgenes harbored by the transgenic micerearrange during B cell differentiation, and subsequently undergo classswitching and somatic mutation. Thus, using such a technique, it ispossible to produce therapeutically useful IgG, IgA, IgM and IgEantibodies. For an overview of this technology for producing humanantibodies, see Lonberg and Huszar (1995, Int. Rev. Immunol. 13:65-93).For a detailed discussion of this technology for producing humanantibodies and human monoclonal antibodies and protocols for producingsuch antibodies, see, e.g., PCT publication Nos. WO 98/24893, WO96/34096, and WO 96/33735; and U.S. Pat. Nos. 5,413,923, 5,625,126,5,633,425, 5,569,825, 5,661,016, 5,545,806, 5,814,318, and 5,939,598,which are incorporated by reference herein in their entirety. Othermethods are detailed in the Examples herein. In addition, companies suchas Abgenix, Inc. (Freemont, Calif.) and Genpharm (San Jose, Calif.) canbe engaged to provide human antibodies directed against a selectedantigen using technology similar to that described above.

A chimeric antibody is a molecule in which different portions of theantibody are derived from different immunoglobulin molecules. Methodsfor producing chimeric antibodies are known in the art. See, e.g.,Morrison, 1985, Science 229:1202; Oi et al., 1986, BioTechniques 4:214;Gillies et al., 1989, J. Immunol. Methods 125:191-202; and U.S. Pat.Nos. 5,807,715, 4,816,567, 4,816,397, and 6,331,415, which areincorporated herein by reference in their entirety.

A humanized antibody is an antibody or its variant or fragment thereofwhich is capable of binding to a predetermined antigen and whichcomprises a framework region having substantially the amino acidsequence of a human immunoglobulin and a CDR having substantially theamino acid sequence of a non-human immunoglobulin. A humanized antibodycomprises substantially all of at least one, and typically two, variabledomains (Fab, Fab′, F(ab′)₂, Fabc, Fv) in which all or substantially allof the CDR regions correspond to those of a non human immunoglobulin(e.g., donor antibody) and all or substantially all of the frameworkregions are those of a human immunoglobulin consensus sequence. Incertain embodiments, a humanized antibody also comprises at least aportion of an immunoglobulin constant region (Fc), typically that of ahuman immunoglobulin. Ordinarily, the antibody will contain both thelight chain as well as at least the variable domain of a heavy chain.The antibody also may include the CH₁, hinge, CH₂, CH₃, and CH₄ regionsof the heavy chain. The humanized antibody can be selected from anyclass of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and anyisotype, including IgG1, IgG2, IgG3 and IgG4. Usually the constantdomain is a complement fixing constant domain where it is desired thatthe humanized antibody exhibit cytotoxic activity, and the class istypically IgG1. Where such cytotoxic activity is not desirable, theconstant domain may be of the IgG2 class. Examples of VL and VH constantdomains that can be used in certain embodiments include, but are notlimited to, C-kappa and C-gamma-1 (nG1m) described in Johnson et al.(1997) J. Infect. Dis. 176, 1215-1224 and those described in U.S. Pat.No. 5,824,307. The humanized antibody may comprise sequences from morethan one class or isotype, and selecting particular constant domains tooptimize desired effector functions is within the ordinary skill in theart. The framework and CDR regions of a humanized antibody need notcorrespond precisely to the parental sequences, e.g., the donor CDR orthe consensus framework may be mutagenized by substitution, insertion ordeletion of at least one residue so that the CDR or framework residue atthat site does not correspond to either the consensus or the importantibody. Such mutations, however, will not be extensive. Usually, atleast 75% of the humanized antibody residues will correspond to those ofthe parental FR and CDR sequences, more often 90%, or greater than 95%.Humanized antibodies can be produced using variety of techniques knownin the art, including but not limited to, CDR-grafting (European PatentNo. EP 239,400; International publication No. WO 91/09967; and U.S. Pat.Nos. 5,225,539, 5,530,101, and 5,585,089), veneering or resurfacing(European Patent Nos. EP 592,106 and EP 519,596; Padlan, 1991, MolecularImmunology 28(4/5):489-498; Studnicka et al., 1994, Protein Engineering7(6):805-814; and Roguska et al., 1994, PNAS 91:969-973), chainshuffling (U.S. Pat. No. 5,565,332), and techniques disclosed in, e.g.,U.S. Pat. Nos. 6,407,213, 5,766,886, WO 9317105, Tan et al., J. Immunol.169:1119 25 (2002), Caldas et al., Protein Eng. 13(5):353-60 (2000),Morea et al., Methods 20(3):267 79 (2000), Baca et al., J. Biol. Chem.272(16):10678-84 (1997), Roguska et al., Protein Eng. 9(10):895 904(1996), Couto et al., Cancer Res. 55 (23 Supp):5973s-5977s (1995), Coutoet al., Cancer Res. 55(8):1717-22 (1995), Sandhu J S, Gene 150(2):409-10(1994), and Pedersen et al., J. Mol. Biol. 235(3):959-73 (1994). Seealso U.S. Patent Pub. No. US 2005/0042664 A1 (Feb. 24, 2005), which isincorporated by reference herein in its entirety. Often, frameworkresidues in the framework regions will be substituted with thecorresponding residue from the CDR donor antibody to alter (e.g.,improve) antigen binding. These framework substitutions are identifiedby methods well known in the art, e.g., by modeling of the interactionsof the CDR and framework residues to identify framework residuesimportant for antigen binding and sequence comparison to identifyunusual framework residues at particular positions. (See, e.g., Queen etal., U.S. Pat. No. 5,585,089; and Reichmann et al., 1988, Nature332:323, which are incorporated herein by reference in theirentireties.)

Single domain antibodies, for example, antibodies lacking the lightchains, can be produced by methods well-known in the art. See Riechmannet al., 1999, J. Immunol. 231:25-38; Nuttall et al., 2000, Curr. Pharm.Biotechnol. 1(3):253-263; Muylderman, 2001, J. Biotechnol. 74(4):277302;U.S. Pat. No. 6,005,079; and International Publication Nos. WO 94/04678,WO 94/25591, and WO 01/44301, each of which is incorporated herein byreference in its entirety.

Further, the antibodies that bind to a C10orf54 antigen can, in turn, beutilized to generate anti-idiotype antibodies that “mimic” an antigenusing techniques well known to those skilled in the art. (See, e.g.,Greenspan & Bona, 1989, FASEB J. 7(5):437-444; and Nissinoff, 1991, J.Immunol. 147(8):2429-2438).

Polynucleotides Encoding an Antibody

Also provided herein are polynucleotides comprising a nucleotidesequence encoding an antibody provided herein that binds to C10orf54(e.g., C10orf54 polypeptide, C10orf54 polypeptide fragment, C10orf54epitope). Also provided herein are polynucleotides that hybridize underhigh stringency, intermediate or lower stringency hybridizationconditions, e.g., as defined supra, to polynucleotides that encode aantibody or modified antibody provided herein.

In certain embodiments, nucleic acid molecules provided herein compriseor consist of a nucleic acid sequence encoding a VH and/or VL amino acidsequence disclosed herein, or any combination thereof (e.g., as anucleotide sequence encoding an antibody provided herein, such as afull-length antibody, heavy and/or light chain of an antibody, or asingle chain antibody provided herein).

Recombinant Expression of an Antibody

Recombinant expression of an antibody provided herein (e.g., afull-length antibody, heavy and/or light chain of an antibody, or asingle chain antibody provided herein) that binds to a C10orf54 antigenrequires construction of an expression vector containing apolynucleotide that encodes the antibody. Once a polynucleotide encodingan antibody molecule, heavy or light chain of an antibody, or fragmentthereof (such as that containing the heavy and/or light chain variabledomain) has been obtained, the vector for the production of the antibodymolecule may be produced by recombinant DNA technology using techniqueswell-known in the art. Thus, methods for preparing a protein byexpressing a polynucleotide containing an antibody encoding nucleotidesequence are described herein. Methods which are well known to thoseskilled in the art can be used to construct expression vectorscontaining antibody coding sequences and appropriate transcriptional andtranslational control signals. These methods include, for example, invitro recombinant DNA techniques, synthetic techniques, and in vivogenetic recombination. Thus, also provided herein are replicable vectorscomprising a nucleotide sequence encoding an antibody molecule providedherein, a heavy or light chain of an antibody, a heavy or light chainvariable domain of an antibody or a fragment thereof, or a heavy orlight chain CDR, operably linked to a promoter. Such vectors may includethe nucleotide sequence encoding the constant region of the antibodymolecule (see, e.g., International Publication Nos. WO 86/05807 and WO89/01036; and U.S. Pat. No. 5,122,464) and the variable domain of theantibody may be cloned into such a vector for expression of the entireheavy, the entire light chain, or both the entire heavy and lightchains.

The expression vector is transferred to a host cell by conventionaltechniques and the transfected cells are then cultured by conventionaltechniques to produce an antibody provided herein. Thus, also providedherein are host cells containing a polynucleotide encoding an antibodyprovided herein or fragments thereof, or a heavy or light chain thereof,or fragment thereof, or a single chain antibody provided herein,operably linked to a heterologous promoter. In certain embodiments forthe expression of double-chained antibodies, vectors encoding both theheavy and light chains may be co-expressed in the host cell forexpression of the entire immunoglobulin molecule, as detailed below.

A variety of host-expression vector systems may be utilized to expressthe antibodies provided herein (see, e.g., U.S. Pat. No. 5,807,715).Such host-expression systems represent vehicles by which the codingsequences of interest may be produced and subsequently purified, butalso represent cells which may, when transformed or transfected with theappropriate nucleotide coding sequences, express an antibody providedherein in situ. These include but are not limited to microorganisms suchas bacteria (e.g., E. coli and B. subtilis) transformed with recombinantbacteriophage DNA, plasmid DNA or cosmid DNA expression vectorscontaining antibody coding sequences; yeast (e.g., Saccharomyces pichia)transformed with recombinant yeast expression vectors containingantibody coding sequences; insect cell systems infected with recombinantvirus expression vectors (e.g., baculovirus) containing antibody codingsequences; plant cell systems infected with recombinant virus expressionvectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus,TMV) or transformed with recombinant plasmid expression vectors (e.g.,Ti plasmid) containing antibody coding sequences; or mammalian cellsystems (e.g., COS, CHO, BHK, 293, NS0, and 3T3 cells) harboringrecombinant expression constructs containing promoters derived from thegenome of mammalian cells (e.g., metallothionein promoter) or frommammalian viruses (e.g., the adenovirus late promoter the vaccinia virus7.5K promoter). In certain embodiments, bacterial cells, such asEscherichia coli, or eukaryotic cells, especially for the expression ofwhole recombinant antibody molecule, are used for the expression of arecombinant antibody molecule. For example, mammalian cells such asChinese hamster ovary cells (CHO), in conjunction with a vector such asthe major intermediate early gene promoter element from humancytomegalovirus is an effective expression system for antibodies(Foecking et al., 1986, Gene 45:101; and Cockett et al., 1990,Bio/Technology 8:2). In specific embodiments, antibodies provided hereinare produced in CHO cells. In a specific embodiment, the expression ofnucleotide sequences encoding antibodies provided herein which bind to aC10orf54 antigen is regulated by a constitutive promoter, induciblepromoter or tissue specific promoter.

In bacterial systems, a number of expression vectors may beadvantageously selected depending upon the use intended for the antibodymolecule being expressed. For example, when a large quantity of such anantibody is to be produced, for the generation of pharmaceuticalcompositions of an antibody molecule, vectors which direct theexpression of high levels of fusion protein products that are readilypurified may be desirable. Such vectors include, but are not limited to,the E. coli expression vector pUR278 (Ruther et al., 1983, EMBO12:1791), in which the antibody coding sequence may be ligatedindividually into the vector in frame with the lac Z coding region sothat a fusion protein is produced; pIN vectors (Inouye & Inouye, 1985,Nucleic Acids Res. 13:3101-3109; Van Heeke & Schuster, 1989, J. Biol.Chem. 24:5503-5509); and the like. pGEX vectors may also be used toexpress foreign polypeptides as fusion proteins with glutathione5-transferase (GST). In general, such fusion proteins are soluble andcan easily be purified from lysed cells by adsorption and binding tomatrix glutathione agarose beads followed by elution in the presence offree glutathione. The pGEX vectors are designed to include thrombin orfactor Xa protease cleavage sites so that the cloned target gene productcan be released from the GST moiety.

In an insect system, Autographa californica nuclear polyhedrosis virus(AcNPV) is used as a vector to express foreign genes. The virus grows inSpodoptera frugiperda cells. The antibody coding sequence may be clonedindividually into non-essential regions (for example the polyhedringene) of the virus and placed under control of an AcNPV promoter (forexample the polyhedrin promoter).

In mammalian host cells, a number of viral-based expression systems maybe utilized. In cases where an adenovirus is used as an expressionvector, the antibody coding sequence of interest may be ligated to anadenovirus transcription/translation control complex, e.g., the latepromoter and tripartite leader sequence. This chimeric gene may then beinserted in the adenovirus genome by in vitro or in vivo recombination.Insertion in a non-essential region of the viral genome (e.g., region EIor E3) will result in a recombinant virus that is viable and capable ofexpressing the antibody molecule in infected hosts (e.g., see Logan &Shenk, 1984, Proc. Natl. Acad. Sci. USA 8 1:355-359). Specificinitiation signals may also be required for efficient translation ofinserted antibody coding sequences. These signals include the ATGinitiation codon and adjacent sequences. Furthermore, the initiationcodon must be in phase with the reading frame of the desired codingsequence to ensure translation of the entire insert. These exogenoustranslational control signals and initiation codons can be of a varietyof origins, both natural and synthetic. The efficiency of expression maybe enhanced by the inclusion of appropriate transcription enhancerelements, transcription terminators, etc. (see, e.g., Bittner et al.,1987, Methods in Enzymol. 153:51-544).

In addition, a host cell strain may be chosen which modulates theexpression of the inserted sequences, or modifies and processes the geneproduct in the specific fashion desired. Such modifications (e.g.,glycosylation) and processing (e.g., cleavage) of protein products maybe important for the function of the protein. Different host cells havecharacteristic and specific mechanisms for the post-translationalprocessing and modification of proteins and gene products. Appropriatecell lines or host systems can be chosen to ensure the correctmodification and processing of the foreign protein expressed. To thisend, eukaryotic host cells which possess the cellular machinery forproper processing of the primary transcript, glycosylation, andphosphorylation of the gene product may be used. Such mammalian hostcells include but are not limited to CHO, VERY, BHK, Hela, COS, MDCK,293, 3T3, W138, BT483, Hs578T, HTB2, BT20 and T47D, NS0 (a murinemyeloma cell line that does not endogenously produce any immunoglobulinchains), CRL7030 and HsS78Bst cells. In specific embodiments, fullyhuman, monoclonal anti-C10orf54 antibodies provided herein are producedin mammalian cells, such as CHO cells.

For long-term, high-yield production of recombinant proteins, stableexpression is useful, but not mandatory. For example, cell lines whichstably express the antibody molecule may be engineered. Rather thanusing expression vectors which contain viral origins of replication,host cells can be transformed with DNA controlled by appropriateexpression control elements (e.g., promoter, enhancer, sequences,transcription terminators, polyadenylation sites, etc.), and aselectable marker. Following the introduction of the foreign DNA,engineered cells may be allowed to grow for 1-2 days in an enrichedmedia, and then are switched to a selective media. The selectable markerin the recombinant plasmid confers resistance to the selection andallows cells to stably integrate the plasmid into their chromosomes andgrow to form foci which in turn can be cloned and expanded into celllines. This method may advantageously be used to engineer cell lineswhich express the antibody molecule. Such engineered cell lines may beparticularly useful in screening and evaluation of compositions thatinteract directly or indirectly with the antibody molecule.

A number of selection systems may be used, including but not limited to,the herpes simplex virus thymidine kinase (Wigler et al., 1977, Cell11:223), hypoxanthineguanine phosphoribosyltransferase (Szybalska &Szybalski, 1992, Proc. Natl. Acad. Sci. USA 48:202), and adeninephosphoribosyltransferase (Lowy et al., 1980, Cell 22:8-17) genes can beemployed in tk-, hgprt- or aprt-cells, respectively. Also,antimetabolite resistance can be used as the basis of selection for thefollowing genes: dhfr, which confers resistance to methotrexate (Wigleret al., 1980, Natl. Acad. Sci. USA 77:357; O'Hare et al., 1981, Proc.Natl. Acad. Sci. USA 78:1527); gpt, which confers resistance tomycophenolic acid (Mulligan & Berg, 1981, Proc. Natl. Acad. Sci. USA78:2072); neo, which confers resistance to the aminoglycoside G-418 (Wuand Wu, 1991, Biotherapy 3:87-95; Tolstoshev, 1993, Ann. Rev. Pharmacol.Toxicol. 32:573-596; Mulligan, 1993, Science 260:926-932; and Morgan andAnderson, 1993, Ann. Rev. Biochem. 62:191-217; May, 1993, TIB TECH11(5):155-2 15); and hygro, which confers resistance to hygromycin(Santerre et al., 1984, Gene 30:147). Methods commonly known in the artof recombinant DNA technology may be routinely applied to select thedesired recombinant clone, and such methods are described, for example,in Ausubel et al. (eds.), Current Protocols in Molecular Biology, JohnWiley & Sons, NY (1993); Kriegler, Gene Transfer and Expression, ALaboratory Manual, Stockton Press, NY (1990); and in Chapters 12 and 13,Dracopoli et al. (eds.), Current Protocols in Human Genetics, John Wiley& Sons, N Y (1994); Colberre-Garapin et al., 1981, J. Mol. Biol. 150:1,which are incorporated by reference herein in their entireties.

The expression levels of an antibody molecule can be increased by vectoramplification (for a review, see Bebbington and Hentschel, The use ofvectors based on gene amplification for the expression of cloned genesin mammalian cells in DNA cloning, Vol. 3 (Academic Press, New York,1987)). When a marker in the vector system expressing antibody isamplifiable, increase in the level of inhibitor present in culture ofhost cell will increase the number of copies of the marker gene. Sincethe amplified region is associated with the antibody gene, production ofthe antibody will also increase (Crouse et al., 1983, Mol. Cell. Biol.3:257).

The host cell may be co-transfected with two expression vectors providedherein, the first vector encoding a heavy chain derived polypeptide andthe second vector encoding a light chain derived polypeptide. The twovectors may contain identical selectable markers which enable equalexpression of heavy and light chain polypeptides. Alternatively, asingle vector may be used which encodes, and is capable of expressing,both heavy and light chain polypeptides. In such situations, the lightchain should be placed before the heavy chain to avoid an excess oftoxic free heavy chain (Proudfoot, 1986, Nature 322:52; and Kohler,1980, Proc. Natl. Acad. Sci. USA 77:2197-2199). The coding sequences forthe heavy and light chains may comprise cDNA or genomic DNA.

Once an antibody has been produced by recombinant expression, it may bepurified by any method known in the art for purification of animmunoglobulin molecule, for example, by chromatography (e.g., ionexchange, affinity, particularly by affinity for the specific antigenafter Protein A, and sizing column chromatography), centrifugation,differential solubility, or by any other standard technique for thepurification of proteins. Further, the antibodies provided herein may befused to heterologous polypeptide sequences described herein orotherwise known in the art to facilitate purification.

Kits

Also provided herein is a pharmaceutical pack or kit comprising one ormore containers filled with one or more of the ingredients of thepharmaceutical compositions provided herein, such as one or moreantibodies provided herein. Optionally associated with such container(s)can be a notice in the form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals or biologicalproducts, which notice reflects approval by the agency of manufacture,use or sale for human administration. In some embodiments, the kitcomprises a package insert. The term “package insert” is used to referto instructions customarily included in commercial packages oftherapeutic products, that contain information about the indications,usage, dosage, administration, contraindications and/or warningsconcerning the use of such therapeutic products, as well as instructionsfor use.

Also provided herein are kits that can be used in the above methods. Inone embodiment, a kit comprises an antibody provided herein, such as anisolated antibody, in one or more containers. In a specific embodiment,the kits provided herein contain a substantially isolated C10orf54antigen as a control. In certain embodiments, the kits provided hereinfurther comprise a control antibody which does not react with theC10orf54 antigen. In another specific embodiment, the kits providedherein contain a means for detecting the binding of a modified antibodyto a C10orf54 antigen (e.g., the antibody may be conjugated to adetectable substrate such as a fluorescent compound, an enzymaticsubstrate, a radioactive compound or a luminescent compound, or a secondantibody which recognizes the first antibody may be conjugated to adetectable substrate). In specific embodiments, the kit may include arecombinantly produced or chemically synthesized C10orf54 antigen. TheC10orf54 antigen provided in the kit may also be attached to a solidsupport. In a more specific embodiment the detecting means of the abovedescribed kit includes a solid support to which C10orf54 antigen isattached. Such a kit may also include a non-attached reporter-labeledanti-human antibody. In this embodiment, binding of the antibody to theC10orf54 antigen can be detected by binding of the reporter-labeledantibody.

The following examples are offered by way of illustration, and not byway of limitation.

EXAMPLES Example 1—Identification of C10Orf54 on the Surface of AcuteMyelogenous Leukemia (AML) Tumor Cells

A total of 14 fresh bone marrow mononuclear cells (BMMCs) from patientswith AML were obtained from AllCells and additional 16 frozen patientsamples were from Fred Hutchinson Cancer Research Center (FHCRC). As acontrol, 16 fresh BMMC samples from healthy donors were analyzed. Tomonitor the quality of individual AML samples, hematoxylin and eosinstaining of AML blasts were performed or AML marker expression wasmonitored using flow cytometry/FACS analysis. Sample handling wasoptimized so as to maximally maintain cell viability during sampleisolation. Optimal labeling times for AML samples were determined toallow for efficient labeling without compromise of cellular integrity.

Surface tagged antigen profiling (sTAg) was used to identify andquantitatively profile the repertoire of surface proteins on cells inthe samples. The extracellular domains of proteins associated with thecell membranes of intact primary AML tumor cells were chemically taggedand then chromatographically enriched for tagged proteins using asolid-phase affinity resin. Eluted proteins were stored at −80° C. priorto mass spectrometry analysis as described below.

Proteins enriched by the sTAg method were identified and quantifiedusing high-resolution, shotgun liquid chromatography tandem massspectrometry (MS). A hybrid ThermoFisher LTQ-ORBITRAP VELOS massspectrometer, which combines the sensitivity of a linear ion trap withthe high-resolution and mass accuracy afforded by the revolutionaryorbitrap mass analyzer (Olsen et al., Mol. Cell Proteomics 8:2759-2769,2009) coupled to a nanoflow liquid chromatography apparatus was employedfor shotgun-based, bottoms-up proteomics to determine the identities andquantitative abundance measurements of proteins in the AML cell surfaceenrichment fractions (Yates et al., Annu. Rev. Biomed. Eng. 11:49-79,2009). Tryptic digests from enriched surface proteins were separated byhydrophobicity via online, nanoflow liquid chromatography as peptidemasses and fragmentation patterns were recorded dynamically by the massspectrometer. To determine peptide and protein identities, the raw MSdata were processed using the SEQUEST algorithm executed on afast-processing Sorcerer 2 platform (Lundgren et al., Curr. Protoc.Bioinformatics, Chapter 13: Unit 13.3, 2009), to determine best-fitmatches between experimental fragmentation patterns and those determinedin-silico from the human proteome. Resulting matches were statisticallyvalidated using the PEPTIDEPROPHET (Keller et al., Anal. Chem.74:5383-5392, 2002) and PROTEINPROPHET (Nesvizhskii et al., Anal. Chem.75: 4646-4658, 2003) algorithms as implemented in SCAFFOLD Software(Proteome Software) to ensure the lowest possible false discovery rates(FDR) and thus inclusion of only robustly identified proteins in thecandidate pool.

The relative quantitative levels of identified proteins in the sTAgsamples were determined using the spectral counting method (reviewed inNeilson et al., Proteomics 11:535-553, 2011). Spectral counting is basedon the empirical demonstration that the number of assigned (positivelyidentified) spectra associated with peptides from each proteincorrelates strongly with that protein's relative abundance in theoriginal mixture (Liu et al., Anal. Chem. 76:4193-4201, 2004). Spectralcounts of identified peptides were obtained from the SCAFFOLD Softwareprogram that displays, sorts and filters the results of SEQUEST-searchedmass spectrometry data. Raw spectral counts were transformed to percentNormalized Spectral Abundance Factor (% NSAF) values (Zybailov et al.,J. Proteome Res. 5:2339-2347, 2006) to account for differences inprotein length and variability in total protein concentration. Selectedmonoclonal antibodies were used to validate the proteomic measurementsusing quantitative FACS analysis as an independent, externalconfirmatory measure of the sTAg mass spectrometry-based proteomicprofiling of the primary tumor cell surface expression (see, e.g.,Example 2).

Using sTAg analysis, C10orf54 having the amino acid sequence of SEQ IDNO:1080 was identified as being present on the surface of AML tumorcells. As shown in FIG. 1A, the sTAg method identified C10orf54 in 7 of30 primary AML samples with a median % NSAF of 0.06. In contrast,C10orf54 was not detected in any 16 BMMC samples from healthy donors.The AML benchmark, CD33, was identified in 11 of 30 AML samples with amedian % NSAF of 0.07, and four of 16 normal BMMC samples with a median% NSAF of 0.05. FIG. 1B, shows a subset of the sTAg samples shown inFIG. 1A. Based on this analysis, C10orf54 appears to be comparablyexpressed to CD33 in patient-derived AML specimens and expressed on asignificant portion of AML patients relative to relevant normalcontrols.

Example 2—Expression of C10Orf54 in AML

Flow cytometry studies were conducted with 23 primary and 3 normalBM-MNC samples obtained as described in Example 1 using anti-C10orf54antibodies to analyze the expression profile of C10orf54 in AML.Antibodies were labeled with AF647 or AF488 fluorochromes. Cells werecounted and used at 500000 cells/stain, resuspended in FACS buffer RPMI,4% HIFBS, 0.02% NaN3. Antibodies were incubated for 15 minutes, at roomtemperature in the dark and then analyzed on a MACSQuant (MiltenylBiotec, Auburn, Calif.) instrument. Data analysis was performed usingthe FLOWJO (TreeStar, Ashland, Oreg.) software. Results of FACS analysisusing anti-C10orf54 antibody 76E1 are shown in FIG. 2.

Example 3—Preparation of Monoclonal Antibodies to C10Orf54

Antibodies to C10orf54 were generated using the iTAb platform. In thissystem, a mouse tumor cell line is transduced to stably express thehuman protein and then implanted subcutaneously in syngeneic mice. Themice are treated with anti-CD8 antibody to remove the cell mediatedrejection pathway while leaving the humoral immune response intact.Following this immunization, spenocytes are harvested, and are fused toan immortalized partner cell to generate hybridomas. Antibodies fromthese hybridomas are screened in multiple assays designed to identify adiverse panel of antibodies with good binding properties. The selectedantibodies are then produced for in vivo testing as follows.

Murine sarcoma cell lines that express C10orf54 were prepared by virusinfection of sarcoma cell lines. A PCR-amplified C10orf54 gene wascloned into a murine stem cell virus expression vector with a neomycinresistance gene and sequenced to confirm the identity. To prepare virusparticles, HEK 293t cells with retroviral packaging proteins weretransfected, in the presence of transfection reagent FUGENE HD (Roche),with the retroviral expression vector containing C10orf54. The virusparticles collected from the supernatant of the culture media 48 hoursafter transfection were used to infect the sarcoma cells. After G418selection, stable transfectants were pooled and then cloned by limitingdilution. Clones were then picked and expanded in the presence ofantibiotics. Clones with the highest expression level of C10orf54 asmeasured by flow cytometry were expanded and banked. These cell lineswere then used to immunize the syngeneic mice for antibody productionand in the binding assays for antibody selection as follows.

For immunization, the mouse sarcoma cell line that expresses C10orf54was implanted subcutaneously in 129s6/SvEv mice, which are syngeneicwith the sarcoma line. Mice were boosted with the cell line three daysprior to spleen harvest. Splenocytes were isolated as single cells andfused with SP2-MIL6 cells using PEG1500. Resulting hybridomas wereplated in 384-well plates and allowed to grow for ten days.

Antibodies against C10orf54 were initially selected using a cell-basedenzyme-linked immunosorbant assay (ELISA) to detect binding to C10orf54.For this assay, the C10orf54 expressing sarcoma cells were plated in384-well plates one day prior to assay. Cells were then treated withhybridoma supernatants. Following incubation and wash, the presence ofbound antibody was detected using a peroxidase-conjugated goatanti-mouse IgG antibody (Jackson ImmunResearch Laboratories) followed bya chemiluminescent substrate (ThermoScientific SuperSignal ELISA PicoSubstrate). Hybridomas identified as positive in the initial screen weretransferred to the wells of a 96-well plate. After growth, thesupernatants were tested in a similar assay for confirmation.

The isotype of the antibodies was identified by ELISA by using isotypespecific goat anti-mouse Fc antibodies. For this assay, C10orf54expressing cells were plated in 384-well plates one day prior to assay.Cells were then treated with hybridoma supernatants. Followingincubation and wash, cells were incubated with peroxidase-conjugatedgoat antibody specific for mouse IgG1 or IgG2a (Jackson ImmunResearchLaboratories), followed by a chemiluminescent substrate(ThermoScientific SuperSignal ELISA Pico Substrate).

Concentration of antibody in supernatants found to be positive forbinding to the C10orf54 expressing cells was measured by ELISA.Supernatants were tested at four dilutions. For each antibody, thedilution that generated a value within the linear range of the standardcurve was used to calculate the concentration of the antibody in thesupernatant. Antibody concentration in the supernatants ranged inconcentration from <1 μg/ml to >500 μg/ml, with approximately 300supernatants >10 μg/ml. Twenty-two monoclonal antibodies were selectedfor their binding to C10orf54 and further analyzed in vitro and in vivoas described herein.

Example 4—Preparation of Humanized Antibodies

Murine antibodies prepared as described in Example 3 were selected forsequencing. The selected monoclonal antibodies designated 76E1, 141A and175A were humanized by two methods as follows. The results ofhumanization are shown in FIGS. 3-8.

In a first humanization method, most amino acids in eachcomplementarity-determining region (CDR), as previously identified, inthe variable heavy (VH) and variable light (VL) domain sequence wereconverted to alanine. The resulting sequence for VH and for VL as shownin FIG. 9 was used as input to the human subgroup identificationalgorithm on the website of Dr. Andrew C. R. Martinwww.bioinf.org.uk/abs/; this method is a derivation of Deret, S. et alSUBIM: a Program for Analysing the Kabat Database and Determining theVariability Subgroup of a new Immunoglobulin Sequence Comput Appl Biosci11:435-439 (1995). Antibody 76E1 VH, 141A VH and 175A VH were closest tohuman VH subgroup I, 76E1 VL and 175A VL were closest to human VL kappasubgroup II, and 141A VL was closest to human VL kappa subgroup III. Foreach murine 76E1, 141A and 175A VH and VL sequence, a single human VH orVL germline acceptor sequence was chosen from the corresponding humansubgroup germline sequences and all human joining region sequencescompiled at IMGT® the international ImMunoGeneTics information System®www.imgt.org (founder and director Marie-Paule Lefranc, Montpellier,France).

In a second humanization method (Carter et al., Proc Nati Acad Sci USA89:4285-4289 (1992)), human VH subgroup III germline was used asacceptor for the murine VH sequences of 76E1 VH, 141A VH and 175A VH;human VL subgroup kappa I was used as acceptor for 76E1 VL, 141A VL and175A VL.

Alteration of human germline framework (e.g., non-CDR residues in VH andVL) positions to corresponding parental murine 76E1, 141A or 175Asequence might be required to optimize binding of the humanizedantibody. Potential changes for each humanized sequence are noted inFIGS. 3-8. Potential changes in the CDR sequences of the humanizedantibodies in order to alleviate complications due to deamidation ofsolvent-exposed asparagines, oxidation of solvent-exposed methionines,and formation of isoaspartic acid are also noted in FIGS. 3-8.

Computer-graphics models of murine 76E1, 141A and 175A VH and VL domainswere generated to aid in selection of CDR and framework residues thatmight require alteration. The Swiss-PdB Viewer program was used (Guex, Nand Peitsch, M C SWISS-MODEL and the Swiss-PdB Viewer An environment forcomparative protein modeling. Electrophoresis 18:2714-2723 (1997) Expasywebsite. Crystal structures of antibodies were taken from the ProteinData Bank website (Berman, H M; Westbrook, J; Feng, Z; Gilliland, G;Bhat, T N; Weissig, H; Shindyalov, I N; Bourne P E, The Protein DataBank Nucleic Acids Research 28:235-242 (2000). The sequences ofhumanized 76E1, 141A and 175A VH and VL domains are shown in FIGS. 3-8.

Example 5—Anti-Tumor Activity

Anti-C10orf54 antibodies were tested for their anti-tumor activity in ananimal tumor model. For these studies, the cell line Kasumi-3 (acutemyeloid leukemia), was obtained from ATCC (CRL-2725) and culturedaccording to the suppliers' protocols. Animals were obtained fromTaconic (Hudson, N.Y.). Studies were conducted with anti-C10orf54antibodies in an animal tumor model.

In these experiments, 4-6 week-old immunodeficient NOD-SCID female micewere used for the Kasumi-3 tumor model. Mice were subcutaneouslyinjected on the right flank with 1.2×10⁶ viable cells (Kasumi-3) in amixture of PBS (without magnesium or calcium) and BD Matrigel (BDBiosciences) at a 1:1 ratio. The injected total volume per mouse was 200μl with 50% being Matrigel (BD Biosciences). Once the tumor reached asize between 65-200 mm³ mice were randomized. Antibodies wereadministered weekly at 15 mg/kg for four weeks, bodyweights and tumorsmeasured once and twice weekly, respectively. Tumor volume wascalculated as described (van der Horst et al., 2009, Neoplasia11(4):355-364). Experiments were performed on groups of at least 8animals per experimental point.

Statistical significance between treatment and control groups wascalculated using the Graphpad Prism software package and applyingStudent's two-tailed t-test. A p-value of less than 0.05 was consideredsignificant. The results of three exemplary experiments are shown inTable 11. For Experiment 1, tumor volumes at which treatment wasinitiated were 114.7 mm3 (day 96). For Experiment 2, tumor volumes atwhich treatment was initiated were 114.5 mm3 (day 103). For Experiment3, tumor volumes at which treatment was initiated were 133 mm3 (day 34).

TABLE 11 EXPERIMENT 1 Treatment Volume ± SD [mm³] TGI [%] P-value CTRLIgG 3255 ± 1704 — — 175A 833 ± 429 −77 0.0088 124A 1305 ± 674  −620.0363 33A 1514 ± 1156 −55 0.0447 51A 1668 ± 638  −51 0.0507 46A 1925 ±791  −42 0.0937 26A 1982 ± 997  −41 0.1154 39A 2039 ± 1102 −39 0.1370EXPERIMENT 2 Treatment Volume ± SD [mm³] TGI [%] P-value CTRL IgG 2689 ±866  — — 141A 1271 ± 962  −55 0.0079 164A 1638 ± 553  −41 0.0136 128A2119 ± 1340 −22 0.3585 3210 2588 ± 1371  −4 0.8638 EXPERIMENT 3Treatment Volume ± SD [mm³] TGI [%] P-value CTRL IgG 1961 ± 1060 — —175A 344 ± 841 −81 0.0342

As shown in FIG. 10 (see also, Table 11, Experiment 1), anti-C10orf54antibody treatment induced strong tumor growth inhibition in establishedKasumi-3 tumors. None of the antibody treatments had significant effecton body-weight, which indicates that the antibody treatment was nottoxic. As shown in FIG. 11 (see also, Table 11, Experiment 3), antibodytreatment again with antibody 175A induces strong tumor growthinhibition in established Kasumi-3 tumors.

Example 6—Preparation and Use of Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) were prepared and used in secondary ADCassays and direct ADC assays with antibodies to C10orf54, as illustratedin the following exemplary generic Scheme A:

where the depicted bonds of the maleimide linker-drug conjugateindicates possible sites of attachment to the antibody.

Exemplary antibody-drug conjugates were prepared usingmaleimidocaproyl-monomethylauristatin F (MC-MMAF), as illustrated in thefollowing exemplary Scheme B:

where the depicted bonds of the MC-MMAF linker-drug conjugate indicatespossible sites of attachment to the antibody.

An exemplary synthetic scheme is as follows. In a sterile 1.7 mleppendorf tube, 20 mg of antibody at 20 mg/ml concentration in phosphatebuffered saline (PBS) pH 7.4 (Gibco, Mg and Ca free) was reacted with 1mM diethylene triamine pentaacetic acid (DTPA) as the chelator. Then2.75 eq. of tris(2-carboxyethyl)phosphine hydrochloride solution (TCEPHCl) (Sigma ampule 0.5M concentration) or 50 μL of 100 mM dithiothreitol(DTT) was added for an average drug-antibody ratio (DAR) of 4 drugs perantibody and incubated at 37° C. for 1 hour. Dithiobisnitro-benzoate(DTNB; Ellman's reagent) colorimetric assay was used to assess freethiols available for conjugation (Ellman et al., BiochemicalPharmacology 7:88-95 (1961)). The reduced antibody solution was cooledin an ice-bath at ˜0° C. for 15 minutes. Then 60 μL of MC-MMAF from a 10mM stock solution in DMSO (9.74 mg in 1.074 ml of DMSO for 10 mM) wasadded and incubated on a roller-plate in a refrigerator at 4° C.overnight (or alternatively at 37° C. for 2 hours). The DTNB assay wasrepeated to demonstrate no free thiols remaining (dear means no freethiol and a yellow color indicates remaining free thiols and incompleteconjugation of payload). The concentration of the ADC was obtained viathe NanoDrop spectrophotometer. The ADC was stored at 4° C.

FIG. 12 shows the results of a secondary ADC assay using anti-C10orf54antibodies in a cell viability assay using a C10orf54 expressing sarcomaline. Anti-C10orf54 antibodies were incubated at a 2:1 ratio with asecondary goat anti mouse antibody conjugated with MMAF. Cells wereplated at 1000 cells/well and incubated in the presence of antibodiesfor 72 hours. The C10orf54 expressing sarcoma cells were killed by theanti-C10orf54 antibodies tested in a concentration-dependent manner.

FIGS. 13-14 show the activity of unconjugated and anti-C10orf54antibodies directly conjugated with MMAE in cell viability assays usingC10orf54 expressing sarcoma lines. For these assays, cells may be platedin varying numbers in the wells and are incubated for various times inthe presence or absence of anti-C10orf54 antibodies and ADCs. Forexample, for the assays shown in FIG. 13, cells were plated at 1000cells/well and incubated in the presence of antibodies for 72 hours. Inthese in vitro cell-based assays, the MMAF conjugated anti-C10orf54antibodies killed the sarcoma cells in a concentration-dependent manner.

FIG. 15 shows results of treatment with anti-C10orf54 antibodies andADCs (e.g., unconjugated and MMAF conjugated anti-C10orf54 antibodies)in an animal tumor (e.g., xenograft) model, with C10orf54-expressing andparental sarcoma lines.

Example 7—Methods of Synthesizing Additional Anti-C10Orf54 Antibody-DrugConjugates

Alternatively, antibody-drug conjugates of formulas (Ia) and (Ib) of thepresent disclosure may be prepared using, as illustrated in thefollowing Scheme C and D, respectively:

In Schemes C and D, the depicted bonds of the linker-drug conjugateindicates possible sites of attachment to the antibody.

Antibody-drug conjugates of Schemes C and D may be prepared using, forexample, the exemplary synthetic scheme of Example 6, wheremaleimidocaproyl-monomethylauristatin F (MC-MMAF) is substituted withthe linker-cytotoxin conjugates depicted in the schemes.

Antibody-drug conjugates, as described in this example and herein, areprepared wherein one or more interchain disulfide bonds of the antibody(e.g., four interchain disulfide bonds as depicted in exemplary SchemesC and D above) are conjugated. Antibody-drug conjugates, wherein one ormore of the intrachain disulfide bonds of the antibody are conjugated,as described herein, have a preferred antibody-to-drug ratio of four.

The embodiments of the present invention described above are intended tobe merely exemplary, and those skilled in the art will recognize, or beable to ascertain using no more than routine experimentation, numerousequivalents to the specific procedures described herein. All suchequivalents are considered to be within the scope of the presentinvention and are covered by the following claims. Furthermore, as usedin this specification and claims, the singular forms “a,” “an” and “the”include plural forms unless the content clearly dictates otherwise.Thus, for example, reference to “an antibody” includes a mixture of twoor more such antibodies, and the like. Additionally, ordinarily skilledartisans will recognize that operational sequences must be set forth insome specific order for the purpose of explanation and claiming, but thepresent invention contemplates various changes beyond such specificorder.

The contents of all references described herein are hereby incorporatedby reference.

Other embodiments are within the following claims.

1. An isolated antibody that binds to C10orf54, wherein the antibodycomprises: (a) a heavy chain variable (V_(H)) region comprising: (1) aV_(H) CDR1 having an amino acid sequence selected from the groupconsisting of SEQ ID NOS:36, 30, 59-62, and 33; (2) a V_(H) CDR2 havingan amino acid sequence selected from the group consisting of SEQ IDNOS:37, 101-104, 50, 114, 99, 100, 31, 65-74, 83-90, 95, 321, 322,835-842, 34, 847-858, 49, 886-894, and 1070-1078; and (3) a V_(H) CDR3having an amino acid sequence selected from the group consisting of SEQID NOS:38, 32, 319, 35, and 883-885; and/or (b) a light chain variable(V_(L)) region comprising: (1) a V_(L) CDR1 having an amino acidsequence selected from the group consisting of SEQ ID NOS:45, 253-271,and 42; (2) a V_(L) CDR2 having an amino acid sequence selected from thegroup consisting of SEQ ID NOS:46, 272-275, 40, 843-846, 43, and1045-1048; and (3) a V_(L) CDR3 having an amino acid sequence selectedfrom the group consisting of SEQ ID NOS:47, 41, 44, and 1056-1058. 2.The antibody of claim 1, wherein the antibody is humanized.
 3. Theantibody of claim 1, wherein the V_(H) region further comprises: (1) aV_(H) FR1 having an amino acid sequence selected from the groupconsisting of SEQ ID NOS:51, 105, 55, 115-121, 39, 58, and 895-902; (2)a V_(H) FR2 having an amino acid sequence selected from the groupconsisting of SEQ ID NOS:52, 106, 56, 122-124, 63, 64, and 323-326; (3)a V_(H) FR3 having an amino acid sequence selected from the groupconsisting of SEQ ID NOS:53, 107-113, 57, 125-251, 96-98, 292-318,327-833, 53, 859-882, and 903-1030; and/or (4) a V_(H) FR4 having anamino acid sequence of SEQ ID NO:54 or
 320. 4. The antibody of claim 1,wherein the V_(L) region further comprises: (1) a V_(L) FR1 having anamino acid sequence selected from the group consisting of SEQ ID NOS:75,252, 79, 277-283, 91, 1031-1037, and 1059-1061; (2) a V_(L) FR2 havingan amino acid sequence selected from the group consisting of SEQ IDNOS:76, 80, 284, 92, 1038-1044, and 1062-1067; (3) a V_(L) FR3 having anamino acid sequence selected from the group consisting of SEQ ID NOS:77,276, 81, 285-291, 93, 1049-1055, 1068, and 1069; and/or (4) a V_(L) FR4having an amino acid of SEQ ID NO:78. 5.-11. (canceled)
 12. The antibodyof claim 1, wherein the V_(H) region comprises the amino acid sequenceof SEQ ID NO: 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 and/orthe V_(L) region comprises the amino acid sequence of SEQ ID NO:24, 25,26, 27, 28 or
 29. 13-29. (canceled)
 30. An isolated antibody that bindsto C10orf54, wherein the antibody comprises: (a) a heavy chain variable(V_(H)) region comprising: (1) a V_(H) CDR1 having an amino acidsequence selected from the group consisting of SEQ ID NOS: 36, 1081,1086, 1087, 1092, 30, 1099, 1104, 1105, 1110, 33, 1117, 1122, 1123 and1128; (2) a V_(H) CDR2 having an amino acid sequence selected from thegroup consisting of SEQ ID NOS: 37, 1082, 1088, 1093, 1098, 31, 1100,1106, 1111, 1116, 34, 1118, 1124, 1129 and 1134; and (3) a V_(H) CDR3having an amino acid sequence selected from the group consisting of SEQID NOS: 38, 1083, 1089, 1094, 32, 1101, 1107, 1112, 35, 1119, 1125 and1130; and/or (b) a light chain variable (V_(L)) region comprising: (1) aV_(L) CDR1 having an amino acid sequence selected from the groupconsisting of SEQ ID NOS: 45, 1084, 1090, 1095, 1102, 1108, 1113, 42,1120, 1126 and 1131; (2) a V_(L) CDR2 having an amino acid sequenceselected from the group consisting of SEQ ID NOS: 46, 1085, 1096, 40,1103, 1114, 43, 1121 and 1132; and (3) a V_(L) CDR3 having an amino acidsequence selected from the group consisting of SEQ ID NOS: 47, 1091,1097, 41, 1109, 1115, 44, 1127 and
 1133. 31.-49. (canceled)
 50. Anisolated antibody that binds to a C10orf54 epitope, wherein the bindingto the epitope competitively blocks the binding of the antibody of claim1 in a dose-dependent manner.
 51. An antibody of claim 1, wherein theantibody is conjugated or recombinantly fused to a diagnostic agent,detectable agent or therapeutic agent. 52-55. (canceled)
 56. Acomposition comprising the antibody of claim
 1. 57. (canceled)
 58. Anisolated nucleic acid molecule comprising or consisting of a nucleicacid sequence that encodes the V_(H) region or V_(L) region of claim 1.59. A vector comprising the nucleic acid molecule of claim
 58. 60. Ahost cell comprising the vector of claim
 59. 61. A method of producingan antibody comprising culturing the host cell of claim 60 underconditions that promote the production of the antibody.
 62. A method oftreating, preventing or alleviating one or more symptoms of a diseasecomprising administering a therapeutically effective amount of thecomposition of claim 56 to a subject, thereby treating, preventing oralleviating one or more symptoms of the disease. 63-66. (canceled)
 67. Amethod of inhibiting the growth of a cell having cell surface expressionof C10orf54 comprising contacting the cell with an effective amount ofthe composition of claim
 56. 68-69. (canceled)
 70. A method ofmodulating an immune response in a subject comprising administering aneffective amount of the composition of claim 56 to a subject. 71.(canceled)
 72. A method for detecting C10orf54 in a sample comprisingcontacting the sample with the antibody of claim 1, wherein saidantibody is conjugated or recombinantly fused to a cytotoxin or to adetectable agent.
 73. (canceled)
 74. A method of treating cancercomprising administering to a subject a therapeutically effective amountof an anti-C10orf54 antibody or an antibody-drug conjugate comprising ananti-C10orf54 antibody, wherein the anti-C10orf54 antibody is theanti-C10orf54 antibody of claim
 1. 75. A method of killing a tumor cellcomprising contacting a C10orf54-expressing tumor cell with an amount ofan anti-C10orf54 antibody or antibody-drug conjugate comprising ananti-C10orf54 antibody effective to kill the tumor cell, wherein theanti-C10orf54 antibody is the anti-C10orf54 antibody of claim
 1. 76. Akit comprising the antibody of claim
 1. 77. (canceled)
 78. Anantibody-drug conjugate of the following formulas (Ia) or (Ib):

or a pharmaceutically acceptable salt thereof; wherein: A is an antibodyor antibody fragment according to claim 1; the two depicted cysteineresidues are from an opened cysteine-cysteine disulfide bond in A; eachX and X′ is independently O, S, NH, or NR¹ wherein R¹ is C₁₋₆ alkyl;W_(a) is —N—, —CH—, —CHCH₂—, ═C(R²)—, or ═CHCH(R²)—; W_(b)—NH—, —N(R¹)—,—CH₂—, —CH₂—NH—, —CH₂—N(R¹)—, —CH₂CH₂—, —CH(R²)—, or —CH₂CH(R²)—;wherein R¹ and R² are independently C₁₋₆ alkyl; CTX is a cytotoxin; R isany chemical group; or R is absent; each L¹, L² and L³ is independentlya linker selected from the group consisting of —O—, —C(O)—, —S—, —S(O)—,—S(O)₂—, —NH—, —NCH₃—, —(CH₂)_(q)—, —NH(CH₂)₂NH—, —OC(O)—, —CO₂—,—NHCH₂CH₂C(O)—, —C(O)NHCH₂CH₂NH—, —NHCH₂C(O)—, —NHC(O)—, —C(O)NH—,—NCH₃C(O)—, —C(O)NCH₃—, —(CH₂CH₂O)_(p), —(CH₂CH₂O)_(p)CH₂CH₂—,—CH₂CH₂—(CH₂CH₂O)_(p)—, —OCH(CH₂O—)₂, -(AA)_(r)-, cyclopentanyl,cyclohexanyl, unsubstituted phenylenyl, and phenylenyl substituted by 1or 2 substituents selected from the group consisting of halo, CF₃—,CF₃O—, CH₃O—, —C(O)OH, —C(O)OC₁₋₃ alkyl, —C(O)CH₃, —CN, —NH—, —NH₂, —O—,—OH, —NHCH₃, —N(CH₃)₂, and C₁₋₃ alkyl; a, b and c are each independentlyan integer of 0, 1, 2 or 3, provided that at least one of a, b or c is1; each k and k′ is independently an integer of 0 or 1; each p isindependently an integer of 1 to 14; each q is independently an integerfrom 1 to 12; each AA is independently an amino acid; each r is 1 to 12;m is an integer of 1 to 4; n is an integer of 1 to 4; and the

bond represents a single or a double bond. 79-83. (canceled)